Proteinopathy

{{short description|Diseases caused by abnormal protein structure}} {{Infobox medical condition (new) | name = | synonym = | image = File:Proteopathy Abeta deposits in Alzheimer disease.jpg | image_size = | alt = | caption = Micrograph of a section of the cerebral cortex from a person with Alzheimer's disease, immunostained with an antibody to amyloid beta (brown), a protein fragment that accumulates in amyloid plaques and cerebral amyloid angiopathy. 10X microscope objective. | pronounce = | specialty =  | symptoms = | complications = | onset = | duration = | types = | causes = | risks = | diagnosis = | differential = | prevention = | treatment = | medication = | prognosis = | frequency = | deaths = }}

A '''proteinopathy''' ([''pref''. protein]; -pathy [''suff''. disease]; '''proteinopathies''' ''pl''.; '''proteinopathic''' ''adj''), or '''proteopathy''', '''protein conformational disorder''', or '''protein misfolding disease''', is a class of diseases in which certain proteins become misfolded. The structurally abnormal proteins disrupt the function of cells in tissues and organs.<ref name="Walker1">{{cite journal | vauthors = Walker LC, LeVine H | title = The cerebral proteopathies | journal = Neurobiology of Aging | volume = 21 | issue = 4 | pages = 559–61 | year = 2000 | pmid = 10924770 | doi = 10.1016/S0197-4580(00)00160-3 | s2cid = 54314137 }}</ref><ref name="Walker2">{{cite journal | vauthors = Walker LC, LeVine H | title = The cerebral proteopathies: neurodegenerative disorders of protein conformation and assembly | journal = Molecular Neurobiology | volume = 21 | issue = 1–2 | pages = 83–95 | year = 2000 | pmid = 11327151 | doi = 10.1385/MN:21:1-2:083 | s2cid = 32618330 }}</ref>

Often the proteins fail to fold into their normal configuration; in this misfolded state, the proteins can become toxic in some way (a toxic gain-of-function) or they can lose their normal function.<ref name="Luheshi">{{cite journal | vauthors = Luheshi LM, Crowther DC, Dobson CM | title = Protein misfolding and disease: from the test tube to the organism | journal = Current Opinion in Chemical Biology | volume = 12 | issue = 1 | pages = 25–31 | date = February 2008 | pmid = 18295611 | doi = 10.1016/j.cbpa.2008.02.011 }}</ref> The proteinopathies include such diseases as Creutzfeldt–Jakob disease (and a variant associated with mad cow disease) and other prion diseases, Alzheimer's disease, Parkinson's disease, amyloidosis, multiple system atrophy, and a wide range of other disorders.<ref name="Walker2" /><ref name="Chiti">{{cite journal | vauthors = Chiti F, Dobson CM | title = Protein misfolding, functional amyloid, and human disease | journal = Annual Review of Biochemistry | volume = 75 | issue = 1 | pages = 333–66 | year = 2006 | pmid = 16756495 | doi = 10.1146/annurev.biochem.75.101304.123901 | s2cid = 23797549 }}</ref><ref name="Carrell">{{cite journal | vauthors = Carrell RW, Lomas DA | title = Conformational disease | journal = Lancet | volume = 350 | issue = 9071 | pages = 134–8 | date = July 1997 | pmid = 9228977 | doi = 10.1016/S0140-6736(97)02073-4 | s2cid = 39124185 }}</ref><ref name = "Westermark">{{cite journal | vauthors = Westermark P, Benson MD, Buxbaum JN, Cohen AS, Frangione B, Ikeda S, Masters CL, Merlini G, Saraiva MJ, Sipe JD | title = A primer of amyloid nomenclature | journal = Amyloid | volume = 14 | issue = 3 | pages = 179–83 | date = September 2007 | pmid = 17701465 | doi = 10.1080/13506120701460923 | s2cid = 12480248 }}</ref><ref>{{cite journal | vauthors = Westermark GT, Fändrich M, Lundmark K, Westermark P | title = Noncerebral Amyloidoses: Aspects on Seeding, Cross-Seeding, and Transmission | journal = Cold Spring Harbor Perspectives in Medicine | volume = 8 | issue = 1 | article-number = a024323 | date = January 2018 | pmid = 28108533 | doi = 10.1101/cshperspect.a024323 | pmc = 5749146 | doi-access = free }}</ref><ref name="Prusiner 2013">{{cite journal | vauthors = Prusiner SB | title = Biology and genetics of prions causing neurodegeneration | journal = Annual Review of Genetics | volume = 47 | pages = 601–23 | date = 2013 | pmid = 24274755 | pmc = 4010318 | doi = 10.1146/annurev-genet-110711-155524 }}</ref> The term ''proteopathy'' was first proposed in 2000 by Lary Walker and Harry LeVine.<ref name="Walker1">{{cite journal | vauthors = Walker LC, LeVine H | title = The cerebral proteopathies | journal = Neurobiology of Aging | volume = 21 | issue = 4 | pages = 559–61 | year = 2000 | pmid = 10924770 | doi = 10.1016/S0197-4580(00)00160-3 | s2cid = 54314137 }}</ref>

The concept of proteopathy can trace its origins to the mid-19th century, when, in 1854, Rudolf Virchow coined the term amyloid ("starch-like") to describe a substance in cerebral corpora amylacea that exhibited a chemical reaction resembling that of cellulose. In 1859, Friedreich and Kekulé demonstrated that, rather than consisting of cellulose, "amyloid" actually is rich in protein.<ref name="Sipe">{{cite journal | vauthors = Sipe JD, Cohen AS | title = Review: history of the amyloid fibril | journal = Journal of Structural Biology | volume = 130 | issue = 2–3 | pages = 88–98 | date = June 2000 | pmid = 10940217 | doi = 10.1006/jsbi.2000.4221 }}</ref> Subsequent research has shown that many different proteins can form amyloid, and that all amyloids show birefringence in cross-polarized light after staining with the dye Congo red, as well as a fibrillar ultrastructure when viewed with an electron microscope.<ref name="Sipe"/> However, some proteinaceous lesions lack birefringence and contain few or no classical amyloid fibrils, such as the diffuse deposits of amyloid beta (Aβ) protein in the brains of people with Alzheimer's.<ref name="Wisniewski">{{cite journal | vauthors = Wisniewski HM, Sadowski M, Jakubowska-Sadowska K, Tarnawski M, Wegiel J | title = Diffuse, lake-like amyloid-beta deposits in the parvopyramidal layer of the presubiculum in Alzheimer disease | journal = Journal of Neuropathology and Experimental Neurology | volume = 57 | issue = 7 | pages = 674–83 | date = July 1998 | pmid = 9690671 | doi = 10.1097/00005072-199807000-00004 | doi-access = free }}</ref> Furthermore, evidence has emerged that small, non-fibrillar protein aggregates known as oligomers are toxic to the cells of an affected organ, and that amyloidogenic proteins in their fibrillar form may be relatively benign.<ref name="Glabe">{{cite journal | vauthors = Glabe CG | title = Common mechanisms of amyloid oligomer pathogenesis in degenerative disease | journal = Neurobiology of Aging | volume = 27 | issue = 4 | pages = 570–5 | date = April 2006 | pmid = 16481071 | doi = 10.1016/j.neurobiolaging.2005.04.017 | s2cid = 32899741 }}</ref><ref name="Gadad">{{cite journal | vauthors = Gadad BS, Britton GB, Rao KS | title = Targeting oligomers in neurodegenerative disorders: lessons from α-synuclein, tau, and amyloid-β peptide | journal = Journal of Alzheimer's Disease | volume = 24 | pages = 223–32 | year = 2011 | issue = Suppl 2 | pmid = 21460436 | doi = 10.3233/JAD-2011-110182 }}</ref> [[File:Amyloid Liver Congo Red Bar=100um.jpg|thumb|Micrograph of amyloid in a section of liver that has been stained with the dye Congo red and viewed with crossed polarizing filters, yielding a typical orange-greenish birefringence. 20X microscope objective; the scale bar is 100 microns (0.1mm).]]

==Pathophysiology==

In most, if not all proteinopathies, a change in the 3-dimensional folding conformation increases the tendency of a specific protein to bind to itself.<ref name="Carrell"/> In this aggregated form, the protein is resistant to clearance and can interfere with the normal capacity of the affected organs. In some cases, misfolding of the protein results in a loss of its usual function. For example, cystic fibrosis is caused by a defective cystic fibrosis transmembrane conductance regulator (CFTR) protein,<ref name="Luheshi"/> and in amyotrophic lateral sclerosis / frontotemporal lobar degeneration (FTLD), certain gene-regulating proteins inappropriately aggregate in the cytoplasm, and thus are unable to perform their normal tasks within the nucleus.<ref name="ItoSuzuki">{{cite journal | vauthors = Ito D, Suzuki N | title = Conjoint pathologic cascades mediated by ALS/FTLD-U linked RNA-binding proteins TDP-43 and FUS | journal = Neurology | volume = 77 | issue = 17 | pages = 1636–43 | date = October 2011 | pmid = 21956718 | pmc = 3198978 | doi = 10.1212/WNL.0b013e3182343365 }}</ref><ref name="Wolozin 2015">{{cite book | vauthors = Wolozin B, Apicco D | title = GeNeDis 2014 | chapter = RNA Binding Proteins and the Genesis of Neurodegenerative Diseases | volume = 822 | pages = 11–5 | date = 2015 | pmid = 25416971 | pmc = 4694570 | doi = 10.1007/978-3-319-08927-0_3 | isbn = 978-3-319-08926-3 | series = Advances in Experimental Medicine and Biology | author-link = Benjamin Wolozin }}</ref>

Because proteins share a common structural feature known as the polypeptide backbone, all proteins have the potential to misfold under some circumstances.<ref name="Dobson">{{cite journal | vauthors = Dobson CM | title = Protein misfolding, evolution and disease | journal = Trends in Biochemical Sciences | volume = 24 | issue = 9 | pages = 329–32 | date = September 1999 | pmid = 10470028 | doi = 10.1016/S0968-0004(99)01445-0 }}</ref> However, only a relatively small number of proteins are linked to proteopathic disorders, possibly due to structural idiosyncrasies of the vulnerable proteins. For example, proteins that are normally unfolded or relatively unstable as monomers (that is, as single, unbound protein molecules) are more likely to misfold into an abnormal conformation.<ref name="Carrell"/><ref name="Dobson"/><ref name="Jucker and Walker 2013">{{cite journal | vauthors = Jucker M, Walker LC | title = Self-propagation of pathogenic protein aggregates in neurodegenerative diseases | journal = Nature | volume = 501 | issue = 7465 | pages = 45–51 | date = September 2013 | pmid = 24005412 | pmc = 3963807 | doi = 10.1038/nature12481 | bibcode = 2013Natur.501...45J }}</ref> In nearly all instances, the disease-causing molecular configuration involves an increase in beta-sheet secondary structure of the protein.<ref name="Carrell"/><ref name="Dobson"/><ref name="Selkoe">{{cite journal | vauthors = Selkoe DJ | title = Folding proteins in fatal ways | journal = Nature | volume = 426 | issue = 6968 | pages = 900–4 | date = December 2003 | pmid = 14685251 | doi = 10.1038/nature02264 | bibcode = 2003Natur.426..900S | s2cid = 6451881 }}</ref><ref name="Eisenberg and Jucker 2012">{{cite journal | vauthors = Eisenberg D, Jucker M | title = The amyloid state of proteins in human diseases | journal = Cell | volume = 148 | issue = 6 | pages = 1188–203 | date = March 2012 | pmid = 22424229 | doi = 10.1016/j.cell.2012.02.022 | pmc = 3353745 }}</ref>

The abnormal proteins in some proteopathies have been shown to fold into multiple 3-dimensional shapes; these variant, proteinaceous structures are defined by their different pathogenic, biochemical, and conformational properties.<ref name="Walker LC 2016">{{cite journal | vauthors = Walker LC | title = Proteopathic Strains and the Heterogeneity of Neurodegenerative Diseases | journal = Annual Review of Genetics | volume = 50 | pages = 329–346 | date = November 2016 | pmid = 27893962 | doi = 10.1146/annurev-genet-120215-034943 | pmc = 6690197 }}</ref> They have been most thoroughly studied with regard to prion disease, and are referred to as protein strains.<ref name="Collinge">{{cite journal | vauthors = Collinge J, Clarke AR | title = A general model of prion strains and their pathogenicity | journal = Science | volume = 318 | issue = 5852 | pages = 930–6 | date = November 2007 | pmid = 17991853 | doi = 10.1126/science.1138718 | bibcode = 2007Sci...318..930C | s2cid = 8993435 | doi-access = }}</ref><ref name="Colby">{{cite journal | vauthors = Colby DW, Prusiner SB | title = De novo generation of prion strains | journal = Nature Reviews. Microbiology | volume = 9 | issue = 11 | pages = 771–7 | date = September 2011 | pmid = 21947062 | pmc = 3924856 | doi = 10.1038/nrmicro2650 }}</ref>

[[File:Immunostaining (brown) of alpha-synuclein in Lewy Bodies and Lewy Neurites in the neocortex of a patient with Lewy Body Disease.jpg|thumb|Micrograph of immunostained α-synuclein (brown) in Lewy bodies (large clumps) and Lewy neurites (thread-like structures) in the cerebral cortex of a patient with Lewy body disease, a synucleinopathy. 40X microscope objective.]]

The likelihood that proteinopathy will develop is increased by certain risk factors that promote the self-assembly of a protein. These include destabilizing changes in the primary amino acid sequence of the protein, post-translational modifications (such as hyperphosphorylation), changes in temperature or pH, an increase in production of a protein, or a decrease in its clearance.<ref name="Walker1"/><ref name="Carrell"/><ref name="Dobson"/> Advancing age is a strong risk factor,<ref name="Walker1"/> as is traumatic brain injury.<ref name="DeKosky">{{cite journal | vauthors = DeKosky ST, Ikonomovic MD, Gandy S | title = Traumatic brain injury--football, warfare, and long-term effects | journal = The New England Journal of Medicine | volume = 363 | issue = 14 | pages = 1293–6 | date = September 2010 | pmid = 20879875 | doi = 10.1056/NEJMp1007051 }}</ref><ref name="McKee et al., 2015">{{cite journal | vauthors = McKee AC, Stein TD, Kiernan PT, Alvarez VE | title = The neuropathology of chronic traumatic encephalopathy | journal = Brain Pathology | volume = 25 | issue = 3 | pages = 350–64 | date = May 2015 | pmid = 25904048 | doi = 10.1111/bpa.12248 | pmc = 4526170 }}</ref> In the aging brain, multiple proteopathies can overlap.<ref name="Nelson PT et al. 2012">{{cite journal | vauthors = Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, Castellani RJ, Crain BJ, Davies P, Del Tredici K, Duyckaerts C, Frosch MP, Haroutunian V, Hof PR, Hulette CM, Hyman BT, Iwatsubo T, Jellinger KA, Jicha GA, Kövari E, Kukull WA, Leverenz JB, Love S, Mackenzie IR, Mann DM, Masliah E, McKee AC, Montine TJ, Morris JC, Schneider JA, Sonnen JA, Thal DR, Trojanowski JQ, Troncoso JC, Wisniewski T, Woltjer RL, Beach TG | title = Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature | journal = Journal of Neuropathology and Experimental Neurology | volume = 71 | issue = 5 | pages = 362–81 | date = May 2012 | pmid = 22487856 | doi = 10.1097/NEN.0b013e31825018f7 | pmc = 3560290 }}</ref> For example, in addition to tauopathy and Aβ-amyloidosis (which coexist as key pathologic features of Alzheimer's disease), many Alzheimer patients have concomitant synucleinopathy (Lewy bodies) in the brain.<ref name="Mrak">{{cite journal | vauthors = Mrak RE, Griffin WS | title = Dementia with Lewy bodies: Definition, diagnosis, and pathogenic relationship to Alzheimer's disease | journal = Neuropsychiatric Disease and Treatment | volume = 3 | issue = 5 | pages = 619–25 | year = 2007 | pmid = 19300591 | pmc = 2656298 }}</ref>

It is hypothesized that chaperones and co-chaperones (proteins that assist protein folding) may antagonize proteotoxicity during aging and in protein misfolding-diseases to maintain proteostasis.<ref>{{cite journal | vauthors = Douglas PM, Summers DW, Cyr DM | title = Molecular chaperones antagonize proteotoxicity by differentially modulating protein aggregation pathways | journal = Prion | volume = 3 | issue = 2 | pages = 51–8 | year = 2009 | pmid = 19421006 | pmc = 2712599 | doi = 10.4161/pri.3.2.8587 }}</ref><ref name="Brehme">{{cite journal | vauthors = Brehme M, Voisine C, Rolland T, Wachi S, Soper JH, Zhu Y, Orton K, Villella A, Garza D, Vidal M, Ge H, Morimoto RI | title = A chaperome subnetwork safeguards proteostasis in aging and neurodegenerative disease | journal = Cell Reports | volume = 9 | issue = 3 | pages = 1135–50 | date = November 2014 | pmid = 25437566 | pmc = 4255334 | doi = 10.1016/j.celrep.2014.09.042 }}</ref><ref>{{cite journal | vauthors = Brehme M, Voisine C | title = Model systems of protein-misfolding diseases reveal chaperone modifiers of proteotoxicity | journal = Disease Models & Mechanisms | volume = 9 | issue = 8 | pages = 823–38 | date = August 2016 | pmid = 27491084 | pmc = 5007983 | doi = 10.1242/dmm.024703 }}</ref>

==Seeded induction==

Some proteins can be induced to form abnormal assemblies by exposure to the same (or similar) protein that has folded into a disease-causing conformation, a process called 'seeding' or 'permissive templating'.<ref name="Hardy">{{cite journal | vauthors = Hardy J | title = Expression of normal sequence pathogenic proteins for neurodegenerative disease contributes to disease risk: 'permissive templating' as a general mechanism underlying neurodegeneration | journal = Biochemical Society Transactions | volume = 33 | issue = Pt 4 | pages = 578–81 | date = August 2005 | pmid = 16042548 | doi = 10.1042/BST0330578 }}</ref><ref name="Walker3">{{cite journal | vauthors = Walker LC, Levine H, Mattson MP, Jucker M | title = Inducible proteopathies | journal = Trends in Neurosciences | volume = 29 | issue = 8 | pages = 438–43 | date = August 2006 | pmid = 16806508 | doi = 10.1016/j.tins.2006.06.010 | s2cid = 46630402 | pmc = 10725716 }}</ref> In this way, the disease state can be brought about in a susceptible host by the introduction of diseased tissue extract from an affected donor. The best known forms of inducible proteopathy are prion diseases,<ref name="Prusiner">{{cite journal | vauthors = Prusiner SB | title = Shattuck lecture--neurodegenerative diseases and prions | journal = The New England Journal of Medicine | volume = 344 | issue = 20 | pages = 1516–26 | date = May 2001 | pmid = 11357156 | doi = 10.1056/NEJM200105173442006 | doi-access = free }}</ref> which can be transmitted by exposure of a host organism to purified prion protein in a disease-causing conformation.<ref name="Zou">{{cite journal | vauthors = Zou WQ, Gambetti P | title = From microbes to prions the final proof of the prion hypothesis | journal = Cell | volume = 121 | issue = 2 | pages = 155–7 | date = April 2005 | pmid = 15851020 | doi = 10.1016/j.cell.2005.04.002 | doi-access = free }}</ref><ref name="Ma J 2012">{{cite journal | vauthors = Ma J | title = The role of cofactors in prion propagation and infectivity | journal = PLOS Pathogens | volume = 8 | issue = 4 | article-number = e1002589 | date = 2012 | pmid = 22511864 | doi = 10.1371/journal.ppat.1002589 | pmc = 3325206 | doi-access = free }}</ref>

There is now evidence that other proteinopathies can be induced by a similar mechanism, including Aβ amyloidosis, amyloid A (AA) amyloidosis, and apolipoprotein AII amyloidosis,<ref name="Walker3"/><ref name = "Meyer">{{cite journal | vauthors = Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C, Kilger E, Neuenschwander A, Abramowski D, Frey P, Jaton AL, Vigouret JM, Paganetti P, Walsh DM, Mathews PM, Ghiso J, Staufenbiel M, Walker LC, Jucker M | title = Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host | journal = Science | volume = 313 | issue = 5794 | pages = 1781–4 | date = September 2006 | pmid = 16990547 | doi = 10.1126/science.1131864 | bibcode = 2006Sci...313.1781M | s2cid = 27127208 | url = http://infoscience.epfl.ch/record/147290 }}</ref> tauopathy,<ref name="Clavaguera">{{cite journal | vauthors = Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M, Jucker M, Goedert M, Tolnay M | title = Transmission and spreading of tauopathy in transgenic mouse brain | journal = Nature Cell Biology | volume = 11 | issue = 7 | pages = 909–13 | date = July 2009 | pmid = 19503072 | pmc = 2726961 | doi = 10.1038/ncb1901 }}</ref> synucleinopathy,<ref name="Desplats">{{cite journal | vauthors = Desplats P, Lee HJ, Bae EJ, Patrick C, Rockenstein E, Crews L, Spencer B, Masliah E, Lee SJ | title = Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 31 | pages = 13010–5 | date = August 2009 | pmid = 19651612 | pmc = 2722313 | doi = 10.1073/pnas.0903691106 | doi-access = free }}</ref><ref name="Hansen">{{cite journal | vauthors = Hansen C, Angot E, Bergström AL, Steiner JA, Pieri L, Paul G, Outeiro TF, Melki R, Kallunki P, Fog K, Li JY, Brundin P | title = α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells | journal = The Journal of Clinical Investigation | volume = 121 | issue = 2 | pages = 715–25 | date = February 2011 | pmid = 21245577 | pmc = 3026723 | doi = 10.1172/JCI43366 }}</ref><ref name="Kordower1">{{cite journal | vauthors = Kordower JH, Dodiya HB, Kordower AM, Terpstra B, Paumier K, Madhavan L, Sortwell C, Steece-Collier K, Collier TJ | title = Transfer of host-derived α synuclein to grafted dopaminergic neurons in rat | journal = Neurobiology of Disease | volume = 43 | issue = 3 | pages = 552–7 | date = September 2011 | pmid = 21600984 | pmc = 3430516 | doi = 10.1016/j.nbd.2011.05.001 }}</ref><ref name="Kordower2">{{cite journal | vauthors = Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW | title = Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease | journal = Nature Medicine | volume = 14 | issue = 5 | pages = 504–6 | date = May 2008 | pmid = 18391962 | doi = 10.1038/nm1747 | s2cid = 11991816 }}</ref> and the aggregation of superoxide dismutase-1 (SOD1),<ref name="Chia">{{cite journal | vauthors = Chia R, Tattum MH, Jones S, Collinge J, Fisher EM, Jackson GS | title = Superoxide dismutase 1 and tgSOD1 mouse spinal cord seed fibrils, suggesting a propagative cell death mechanism in amyotrophic lateral sclerosis | journal = PLOS ONE | volume = 5 | issue = 5 | article-number = e10627 | date = May 2010 | pmid = 20498711 | pmc = 2869360 | doi = 10.1371/journal.pone.0010627 | editor1-last = Feany | editor1-first = Mel B. | doi-access = free }}</ref><ref name="Munch">{{cite journal | vauthors = Münch C, O'Brien J, Bertolotti A | title = Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 9 | pages = 3548–53 | date = March 2011 | pmid = 21321227 | pmc = 3048161 | doi = 10.1073/pnas.1017275108 | bibcode = 2011PNAS..108.3548M | doi-access = free }}</ref> polyglutamine,<ref name="Ren">{{cite journal | vauthors = Ren PH, Lauckner JE, Kachirskaia I, Heuser JE, Melki R, Kopito RR | title = Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates | journal = Nature Cell Biology | volume = 11 | issue = 2 | pages = 219–25 | date = February 2009 | pmid = 19151706 | pmc = 2757079 | doi = 10.1038/ncb1830 }}</ref><ref name="Pearce and Kopito">{{cite journal | vauthors = Pearce MM, Kopito RR | title = Prion-Like Characteristics of Polyglutamine-Containing Proteins | journal = Cold Spring Harbor Perspectives in Medicine | volume = 8 | issue = 2 | article-number = a024257 | date = February 2018 | pmid = 28096245 | doi = 10.1101/cshperspect.a024257 | pmc = 5793740 }}</ref> and TAR DNA-binding protein-43 (TDP-43).<ref name="Furukawa">{{cite journal | vauthors = Furukawa Y, Kaneko K, Watanabe S, Yamanaka K, Nukina N | title = A seeding reaction recapitulates intracellular formation of Sarkosyl-insoluble transactivation response element (TAR) DNA-binding protein-43 inclusions | journal = The Journal of Biological Chemistry | volume = 286 | issue = 21 | pages = 18664–72 | date = May 2011 | pmid = 21454603 | pmc = 3099683 | doi = 10.1074/jbc.M111.231209 | doi-access = free }}</ref>

In all of these instances, an aberrant form of the protein itself appears to be the pathogenic agent. In some cases, the deposition of one type of protein can be experimentally induced by aggregated assemblies of other proteins that are rich in β-sheet structure, possibly because of structural complementarity of the protein molecules. For example, AA amyloidosis can be stimulated in mice by such diverse macromolecules as silk, the yeast amyloid Sup35, and curli fibrils from the bacterium ''Escherichia coli''.<ref name="Lundmark">{{cite journal | vauthors = Lundmark K, Westermark GT, Olsén A, Westermark P | title = Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: Cross-seeding as a disease mechanism | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 17 | pages = 6098–102 | date = April 2005 | pmid = 15829582 | pmc = 1087940 | doi = 10.1073/pnas.0501814102 | bibcode = 2005PNAS..102.6098L | doi-access = free }}</ref> AII amyloid can be induced in mice by a variety of β-sheet rich amyloid fibrils,<ref name="Fu">{{cite journal | vauthors = Fu X, Korenaga T, Fu L, Xing Y, Guo Z, Matsushita T, Hosokawa M, Naiki H, Baba S, Kawata Y, Ikeda S, Ishihara T, Mori M, Higuchi K | title = Induction of AApoAII amyloidosis by various heterogeneous amyloid fibrils | journal = FEBS Letters | volume = 563 | issue = 1–3 | pages = 179–84 | date = April 2004 | pmid = 15063745 | doi = 10.1016/S0014-5793(04)00295-9 | doi-access = free | bibcode = 2004FEBSL.563..179F }}</ref> and cerebral tauopathy can be induced by brain extracts that are rich in aggregated Aβ.<ref name="Bolmont">{{cite journal | vauthors = Bolmont T, Clavaguera F, Meyer-Luehmann M, Herzig MC, Radde R, Staufenbiel M, Lewis J, Hutton M, Tolnay M, Jucker M | title = Induction of tau pathology by intracerebral infusion of amyloid-beta -containing brain extract and by amyloid-beta deposition in APP x Tau transgenic mice | journal = The American Journal of Pathology | volume = 171 | issue = 6 | pages = 2012–20 | date = December 2007 | pmid = 18055549 | pmc = 2111123 | doi = 10.2353/ajpath.2007.070403 }}</ref> There is also experimental evidence for cross-seeding between prion protein and Aβ.<ref name="Morales">{{cite journal | vauthors = Morales R, Estrada LD, Diaz-Espinoza R, Morales-Scheihing D, Jara MC, Castilla J, Soto C | title = Molecular cross talk between misfolded proteins in animal models of Alzheimer's and prion diseases | journal = The Journal of Neuroscience | volume = 30 | issue = 13 | pages = 4528–35 | date = March 2010 | pmid = 20357103 | pmc = 2859074 | doi = 10.1523/JNEUROSCI.5924-09.2010 }}</ref> In general, such heterologous seeding is less efficient than is seeding by a corrupted form of the same protein.

==List of proteinopathies==

{| class="wikitable" border="1" |- |'''Proteinopathy''' | '''Major aggregating protein''' |- | Alzheimer's disease<ref name="Jucker and Walker 2013">{{cite journal | vauthors = Jucker M, Walker LC | title = Self-propagation of pathogenic protein aggregates in neurodegenerative diseases | journal = Nature | volume = 501 | issue = 7465 | pages = 45–51 | date = September 2013 | pmid = 24005412 | pmc = 3963807 | doi = 10.1038/nature12481 | bibcode = 2013Natur.501...45J }}</ref> | Amyloid β peptide (Aβ); Tau protein (see tauopathies) |- | Cerebral β-amyloid angiopathy<ref name="Revesz 2003">{{cite journal | vauthors = Revesz T, Ghiso J, Lashley T, Plant G, Rostagno A, Frangione B, Holton JL | title = Cerebral amyloid angiopathies: a pathologic, biochemical, and genetic view | journal = Journal of Neuropathology and Experimental Neurology | volume = 62 | issue = 9 | pages = 885–98 | date = September 2003 | pmid = 14533778 | doi = 10.1093/jnen/62.9.885 | doi-access = }}</ref> | Amyloid β peptide (Aβ) |- | Retinal ganglion cell degeneration in glaucoma<ref name="Guo">{{cite journal | vauthors = Guo L, Salt TE, Luong V, Wood N, Cheung W, Maass A, Ferrari G, Russo-Marie F, Sillito AM, Cheetham ME, Moss SE, Fitzke FW, Cordeiro MF | title = Targeting amyloid-beta in glaucoma treatment | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 33 | pages = 13444–9 | date = August 2007 | pmid = 17684098 | pmc = 1940230 | doi = 10.1073/pnas.0703707104 | bibcode = 2007PNAS..10413444G | doi-access = free }}</ref> | Amyloid β peptide (Aβ) |- | Prion diseases (multiple)<ref name="Prusiner book 2004">{{cite book|last1=Prusiner|first1=SB|title=Prion Biology and Diseases|date=2004|publisher=Cold Spring Harbor Laboratory Press|location=Cold Spring Harbor, NY|isbn=0-87969-693-1|edition=2}}</ref> | Prion protein |- | Parkinson's disease and other synucleinopathies (multiple)<ref name="Goedert LB 2013">{{cite journal | vauthors = Goedert M, Spillantini MG, Del Tredici K, Braak H | title = 100 years of Lewy pathology | journal = Nature Reviews. Neurology | volume = 9 | issue = 1 | pages = 13–24 | date = January 2013 | pmid = 23183883 | doi = 10.1038/nrneurol.2012.242 | s2cid = 12590215 }}</ref> | α-Synuclein |- | Tauopathies (multiple)<ref name="Clavaguera tau rev 2015">{{cite journal | vauthors = Clavaguera F, Hench J, Goedert M, Tolnay M | title = Invited review: Prion-like transmission and spreading of tau pathology | journal = Neuropathology and Applied Neurobiology | volume = 41 | issue = 1 | pages = 47–58 | date = February 2015 | pmid = 25399729 | doi = 10.1111/nan.12197 | s2cid = 45101893 }}</ref> | Microtubule-associated protein tau (Tau protein) |- | Frontotemporal lobar degeneration (FTLD) (Ubi+, Tau-)<ref name="Mann Snowden 2017">{{cite journal | vauthors = Mann DM, Snowden JS | title = Frontotemporal lobar degeneration: Pathogenesis, pathology and pathways to phenotype | journal = Brain Pathology | volume = 27 | issue = 6 | pages = 723–736 | date = November 2017 | pmid = 28100023 | doi = 10.1111/bpa.12486 | pmc = 8029341 }}</ref> | TDP-43 |- | FTLD–FUS<ref name="Mann Snowden 2017">{{cite journal | vauthors = Mann DM, Snowden JS | title = Frontotemporal lobar degeneration: Pathogenesis, pathology and pathways to phenotype | journal = Brain Pathology | volume = 27 | issue = 6 | pages = 723–736 | date = November 2017 | pmid = 28100023 | doi = 10.1111/bpa.12486 | pmc = 8029341 }}</ref> | Fused in sarcoma (FUS) protein |- | FTLD-TAF15<ref name="Tetter 2024">{{cite journal | vauthors = Tetter S, Arseni D, Murzin AG, Buhidma Y, Peak-Chew SY, Garringer HJ, Newell KL, Vidal R, Apostolova LG, Lashley T, Ghetti B, Ryskeldi-Falcon B | date = 2024 | title = TAF15 amyloid filaments in frontotemporal lobar degeneration | journal = Nature | volume = 625 | issue = 7994 | pages = 345-351 | doi = 10.1038/s41586-023-06801-2 | pmc = 10781619 | pmid = 38057661}}</ref> | TATA-binding protein-associated factor 15 (TAF15) |- | Amyotrophic lateral sclerosis (ALS)<ref name="Grad 2015">{{cite journal | vauthors = Grad LI, Fernando SM, Cashman NR | title = From molecule to molecule and cell to cell: prion-like mechanisms in amyotrophic lateral sclerosis | journal = Neurobiology of Disease | volume = 77 | pages = 257–65 | date = May 2015 | pmid = 25701498 | doi = 10.1016/j.nbd.2015.02.009 | s2cid = 18510138 }}</ref><ref name="Ludolph 2012">{{cite journal | vauthors = Ludolph AC, Brettschneider J, Weishaupt JH | title = Amyotrophic lateral sclerosis | journal = Current Opinion in Neurology | volume = 25 | issue = 5 | pages = 530–5 | date = October 2012 | pmid = 22918486 | doi = 10.1097/WCO.0b013e328356d328 }}</ref> | Superoxide dismutase, TDP-43, FUS, C9ORF72, ubiquilin-2 (UBQLN2) |- | Huntington's disease and other trinucleotide repeat disorders (multiple)<ref name="Orr 2007">{{cite journal | vauthors = Orr HT, Zoghbi HY | title = Trinucleotide repeat disorders | journal = Annual Review of Neuroscience | volume = 30 | issue = 1 | pages = 575–621 | date = July 2007 | pmid = 17417937 | doi = 10.1146/annurev.neuro.29.051605.113042 }}</ref><ref name="Almeida 2013">{{cite journal | vauthors = Almeida B, Fernandes S, Abreu IA, Macedo-Ribeiro S | title = Trinucleotide repeats: a structural perspective | journal = Frontiers in Neurology | volume = 4 | page = 76 | date = 2013 | pmid = 23801983 | doi = 10.3389/fneur.2013.00076 | pmc = 3687200 | doi-access = free }}</ref> | Proteins with tandem glutamine expansions |- | Familial British dementia<ref name="Revesz 2003">{{cite journal | vauthors = Revesz T, Ghiso J, Lashley T, Plant G, Rostagno A, Frangione B, Holton JL | title = Cerebral amyloid angiopathies: a pathologic, biochemical, and genetic view | journal = Journal of Neuropathology and Experimental Neurology | volume = 62 | issue = 9 | pages = 885–98 | date = September 2003 | pmid = 14533778 | doi = 10.1093/jnen/62.9.885 | doi-access = }}</ref> | ABri |- | Familial Danish dementia<ref name="Revesz 2003">{{cite journal | vauthors = Revesz T, Ghiso J, Lashley T, Plant G, Rostagno A, Frangione B, Holton JL | title = Cerebral amyloid angiopathies: a pathologic, biochemical, and genetic view | journal = Journal of Neuropathology and Experimental Neurology | volume = 62 | issue = 9 | pages = 885–98 | date = September 2003 | pmid = 14533778 | doi = 10.1093/jnen/62.9.885 | doi-access = }}</ref> | ADan |- | Hereditary cerebral hemorrhage with amyloidosis (Icelandic) (HCHWA-I)<ref name="Revesz 2003">{{cite journal | vauthors = Revesz T, Ghiso J, Lashley T, Plant G, Rostagno A, Frangione B, Holton JL | title = Cerebral amyloid angiopathies: a pathologic, biochemical, and genetic view | journal = Journal of Neuropathology and Experimental Neurology | volume = 62 | issue = 9 | pages = 885–98 | date = September 2003 | pmid = 14533778 | doi = 10.1093/jnen/62.9.885 | doi-access = }}</ref> | Cystatin C |- | CADASIL<ref name="Spinner">{{cite journal | vauthors = Spinner NB | title = CADASIL: Notch signaling defect or protein accumulation problem? | journal = The Journal of Clinical Investigation | volume = 105 | issue = 5 | pages = 561–2 | date = March 2000 | pmid = 10712425 | pmc = 292459 | doi = 10.1172/JCI9511 }}</ref> | Notch3 |- | Alexander disease<ref name="Quinlan">{{cite journal | vauthors = Quinlan RA, Brenner M, Goldman JE, Messing A | title = GFAP and its role in Alexander disease | journal = Experimental Cell Research | volume = 313 | issue = 10 | pages = 2077–87 | date = June 2007 | pmid = 17498694 | pmc = 2702672 | doi = 10.1016/j.yexcr.2007.04.004 }}</ref> | Glial fibrillary acidic protein (GFAP) |- | Pelizaeus-Merzbacher disease | Proteolipid protein (PLP) |- | Seipinopathies<ref name="Ito">{{cite journal | vauthors = Ito D, Suzuki N | title = Seipinopathy: a novel endoplasmic reticulum stress-associated disease | journal = Brain | volume = 132 | issue = Pt 1 | pages = 8–15 | date = January 2009 | pmid = 18790819 | doi = 10.1093/brain/awn216 | doi-access = free }}</ref> | Seipin |- | Familial amyloidotic neuropathy, Senile systemic amyloidosis | Transthyretin<ref name="Sipe 2016">{{cite journal | vauthors = Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P | title = Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines | journal = Amyloid | volume = 23 | issue = 4 | pages = 209–213 | date = December 2016 | pmid = 27884064 | doi = 10.1080/13506129.2016.1257986 | doi-access = free }}</ref> |- | Serpinopathies (multiple)<ref name="Lomas 2002">{{cite journal | vauthors = Lomas DA, Carrell RW | title = Serpinopathies and the conformational dementias | journal = Nature Reviews Genetics | volume = 3 | issue = 10 | pages = 759–68 | date = October 2002 | pmid = 12360234 | doi = 10.1038/nrg907 | s2cid = 21633779 }}</ref> | Serpins |- | AL (light chain) amyloidosis ([http://www.emedicine.com/DERM/topic19.htm primary systemic amyloidosis]) | Monoclonal immunoglobulin light chains<ref name="Sipe 2016">{{cite journal | vauthors = Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P | title = Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines | journal = Amyloid | volume = 23 | issue = 4 | pages = 209–213 | date = December 2016 | pmid = 27884064 | doi = 10.1080/13506129.2016.1257986 | doi-access = free }}</ref> |- | AH (heavy chain) amyloidosis | Immunoglobulin heavy chains<ref name="Sipe 2016">{{cite journal | vauthors = Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P | title = Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines | journal = Amyloid | volume = 23 | issue = 4 | pages = 209–213 | date = December 2016 | pmid = 27884064 | doi = 10.1080/13506129.2016.1257986 | doi-access = free }}</ref> |- | AA (secondary) amyloidosis | Amyloid A protein<ref name="Sipe 2016">{{cite journal | vauthors = Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P | title = Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines | journal = Amyloid | volume = 23 | issue = 4 | pages = 209–213 | date = December 2016 | pmid = 27884064 | doi = 10.1080/13506129.2016.1257986 | doi-access = free }}</ref> |- | Type II diabetes<ref name="Mukherjee 2017">{{cite journal | vauthors = Mukherjee A, Soto C | title = Prion-Like Protein Aggregates and Type 2 Diabetes | journal = Cold Spring Harbor Perspectives in Medicine | volume = 7 | issue = 5 | article-number = a024315 | date = May 2017 | pmid = 28159831 | doi = 10.1101/cshperspect.a024315 | pmc=5411686}}</ref> | Islet amyloid polypeptide (IAPP; amylin) |- | Aortic medial amyloidosis | Medin (lactadherin)<ref name="Sipe 2016">{{cite journal | vauthors = Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P | title = Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines | journal = Amyloid | volume = 23 | issue = 4 | pages = 209–213 | date = December 2016 | pmid = 27884064 | doi = 10.1080/13506129.2016.1257986 | doi-access = free }}</ref> |- | ApoAI amyloidosis | Apolipoprotein AI<ref name="Sipe 2016">{{cite journal | vauthors = Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P | title = Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines | journal = Amyloid | volume = 23 | issue = 4 | pages = 209–213 | date = December 2016 | pmid = 27884064 | doi = 10.1080/13506129.2016.1257986 | doi-access = free }}</ref> |- | ApoAII amyloidosis | Apolipoprotein AII<ref name="Sipe 2016">{{cite journal | vauthors = Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P | title = Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines | journal = Amyloid | volume = 23 | issue = 4 | pages = 209–213 | date = December 2016 | pmid = 27884064 | doi = 10.1080/13506129.2016.1257986 | doi-access = free }}</ref> |- | ApoAIV amyloidosis | Apolipoprotein AIV<ref name="Sipe 2016">{{cite journal | vauthors = Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P | title = Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines | journal = Amyloid | volume = 23 | issue = 4 | pages = 209–213 | date = December 2016 | pmid = 27884064 | doi = 10.1080/13506129.2016.1257986 | doi-access = free }}</ref> |- | Familial amyloidosis of the Finnish type (FAF) | Gelsolin<ref name="Sipe 2016">{{cite journal | vauthors = Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P | title = Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines | journal = Amyloid | volume = 23 | issue = 4 | pages = 209–213 | date = December 2016 | pmid = 27884064 | doi = 10.1080/13506129.2016.1257986 | doi-access = free }}</ref> |- | Lysozyme amyloidosis | Lysozyme<ref name="Sipe 2016">{{cite journal | vauthors = Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P | title = Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines | journal = Amyloid | volume = 23 | issue = 4 | pages = 209–213 | date = December 2016 | pmid = 27884064 | doi = 10.1080/13506129.2016.1257986 | doi-access = free }}</ref> |- | Fibrinogen amyloidosis | Fibrinogen<ref name="Sipe 2016">{{cite journal | vauthors = Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P | title = Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines | journal = Amyloid | volume = 23 | issue = 4 | pages = 209–213 | date = December 2016 | pmid = 27884064 | doi = 10.1080/13506129.2016.1257986 | doi-access = free }}</ref> |- | Dialysis amyloidosis | Beta-2 microglobulin<ref name="Sipe 2016">{{cite journal | vauthors = Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P | title = Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines | journal = Amyloid | volume = 23 | issue = 4 | pages = 209–213 | date = December 2016 | pmid = 27884064 | doi = 10.1080/13506129.2016.1257986 | doi-access = free }}</ref> |- | Inclusion body myositis/myopathy<ref name="Askanas 2006">{{cite journal | vauthors = Askanas V, Engel WK | title = Inclusion-body myositis: a myodegenerative conformational disorder associated with Abeta, protein misfolding, and proteasome inhibition | journal = Neurology | volume = 66 | issue = 2 Suppl 1 | pages = S39-48 | date = January 2006 | pmid = 16432144 | doi = 10.1212/01.wnl.0000192128.13875.1e | s2cid = 24365234 }}</ref> | Amyloid β peptide (Aβ) |- | Cataracts<ref name="Ecroyd 2008">{{cite journal | vauthors = Ecroyd H, Carver JA | title = Crystallin proteins and amyloid fibrils | journal = Cellular and Molecular Life Sciences | volume = 66 | issue = 1 | pages = 62–81 | date = January 2009 | pmid = 18810322 | doi = 10.1007/s00018-008-8327-4 | s2cid = 6580402 | url = https://ro.uow.edu.au/cgi/viewcontent.cgi?article=1967&context=scipapers | access-date = 2021-09-15 | archive-date = 2018-07-23 | archive-url = https://web.archive.org/web/20180723043635/http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1967&context=scipapers | url-status = live | pmc = 11131532 }}</ref> | Crystallins |- | Retinitis pigmentosa with rhodopsin mutations<ref name="Surguchev">{{cite journal | vauthors = Surguchev A, Surguchov A | title = Conformational diseases: looking into the eyes | journal = Brain Research Bulletin | volume = 81 | issue = 1 | pages = 12–24 | date = January 2010 | pmid = 19808079 | doi = 10.1016/j.brainresbull.2009.09.015 | s2cid = 38832894 }}</ref> | rhodopsin |- | Medullary thyroid carcinoma | Calcitonin<ref name="Sipe 2016">{{cite journal | vauthors = Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P | title = Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines | journal = Amyloid | volume = 23 | issue = 4 | pages = 209–213 | date = December 2016 | pmid = 27884064 | doi = 10.1080/13506129.2016.1257986 | doi-access = free }}</ref> |- | Cardiac atrial amyloidosis | Atrial natriuretic factor<ref name="Sipe 2016">{{cite journal | vauthors = Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P | title = Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines | journal = Amyloid | volume = 23 | issue = 4 | pages = 209–213 | date = December 2016 | pmid = 27884064 | doi = 10.1080/13506129.2016.1257986 | doi-access = free }}</ref> |- | Pituitary prolactinoma | Prolactin<ref name="Sipe 2016">{{cite journal | vauthors = Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P | title = Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines | journal = Amyloid | volume = 23 | issue = 4 | pages = 209–213 | date = December 2016 | pmid = 27884064 | doi = 10.1080/13506129.2016.1257986 | doi-access = free }}</ref> |- | Hereditary lattice corneal dystrophy | Keratoepithelin<ref name="Sipe 2016">{{cite journal | vauthors = Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P | title = Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines | journal = Amyloid | volume = 23 | issue = 4 | pages = 209–213 | date = December 2016 | pmid = 27884064 | doi = 10.1080/13506129.2016.1257986 | doi-access = free }}</ref> |- | Cutaneous lichen amyloidosis<ref name="Huilgol 1998">{{cite journal | vauthors = Huilgol SC, Ramnarain N, Carrington P, Leigh IM, Black MM | title = Cytokeratins in primary cutaneous amyloidosis | journal = The Australasian Journal of Dermatology | volume = 39 | issue = 2 | pages = 81–5 | date = May 1998 | pmid = 9611375 | doi = 10.1111/j.1440-0960.1998.tb01253.x | s2cid = 25820489 }}</ref> | Keratins |- | Mallory bodies<ref name="Janig 2005">{{cite journal | vauthors = Janig E, Stumptner C, Fuchsbichler A, Denk H, Zatloukal K | title = Interaction of stress proteins with misfolded keratins | journal = European Journal of Cell Biology | volume = 84 | issue = 2–3 | pages = 329–39 | date = March 2005 | pmid = 15819411 | doi = 10.1016/j.ejcb.2004.12.018 }}</ref> | Keratin intermediate filament proteins |- | Corneal lactoferrin amyloidosis | Lactoferrin<ref name="Sipe 2016">{{cite journal | vauthors = Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P | title = Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines | journal = Amyloid | volume = 23 | issue = 4 | pages = 209–213 | date = December 2016 | pmid = 27884064 | doi = 10.1080/13506129.2016.1257986 | doi-access = free }}</ref> |- | Pulmonary alveolar proteinosis | Surfactant protein C (SP-C)<ref name="Sipe 2016">{{cite journal | vauthors = Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P | title = Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines | journal = Amyloid | volume = 23 | issue = 4 | pages = 209–213 | date = December 2016 | pmid = 27884064 | doi = 10.1080/13506129.2016.1257986 | doi-access = free }}</ref> |- | Odontogenic (Pindborg) tumor amyloid | Odontogenic ameloblast-associated protein<ref name="Sipe 2016">{{cite journal | vauthors = Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P | title = Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines | journal = Amyloid | volume = 23 | issue = 4 | pages = 209–213 | date = December 2016 | pmid = 27884064 | doi = 10.1080/13506129.2016.1257986 | doi-access = free }}</ref> |- | Seminal vesicle amyloid | Semenogelin I<ref name="Sipe 2016">{{cite journal | vauthors = Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P | title = Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines | journal = Amyloid | volume = 23 | issue = 4 | pages = 209–213 | date = December 2016 | pmid = 27884064 | doi = 10.1080/13506129.2016.1257986 | doi-access = free }}</ref> |- | Apolipoprotein C2 amyloidosis | Apolipoprotein C2 (ApoC2)<ref name="Sipe 2016">{{cite journal | vauthors = Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P | title = Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines | journal = Amyloid | volume = 23 | issue = 4 | pages = 209–213 | date = December 2016 | pmid = 27884064 | doi = 10.1080/13506129.2016.1257986 | doi-access = free }}</ref> |- | Apolipoprotein C3 amyloidosis | Apolipoprotein C3 (ApoC3)<ref name="Sipe 2016">{{cite journal | vauthors = Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P | title = Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines | journal = Amyloid | volume = 23 | issue = 4 | pages = 209–213 | date = December 2016 | pmid = 27884064 | doi = 10.1080/13506129.2016.1257986 | doi-access = free }}</ref> |- | Lect2 amyloidosis | Leukocyte chemotactic factor-2 (Lect2)<ref name="Sipe 2016">{{cite journal | vauthors = Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P | title = Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines | journal = Amyloid | volume = 23 | issue = 4 | pages = 209–213 | date = December 2016 | pmid = 27884064 | doi = 10.1080/13506129.2016.1257986 | doi-access = free }}</ref> |- | Insulin amyloidosis | Insulin<ref name="Sipe 2016">{{cite journal | vauthors = Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P | title = Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines | journal = Amyloid | volume = 23 | issue = 4 | pages = 209–213 | date = December 2016 | pmid = 27884064 | doi = 10.1080/13506129.2016.1257986 | doi-access = free }}</ref> |- | Galectin-7 amyloidosis (primary localized cutaneous amyloidosis) | Galectin-7 (Gal7)<ref name="Sipe 2016">{{cite journal | vauthors = Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P | title = Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines | journal = Amyloid | volume = 23 | issue = 4 | pages = 209–213 | date = December 2016 | pmid = 27884064 | doi = 10.1080/13506129.2016.1257986 | doi-access = free }}</ref> |- | Corneodesmosin amyloidosis | Corneodesmosin<ref name="Sipe 2016">{{cite journal | vauthors = Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P | title = Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines | journal = Amyloid | volume = 23 | issue = 4 | pages = 209–213 | date = December 2016 | pmid = 27884064 | doi = 10.1080/13506129.2016.1257986 | doi-access = free }}</ref> |- | Enfuvirtide amyloidosis<ref name="D'Souza 2014">{{cite journal | vauthors = D'Souza A, Theis JD, Vrana JA, Dogan A | title = Pharmaceutical amyloidosis associated with subcutaneous insulin and enfuvirtide administration | journal = Amyloid | volume = 21 | issue = 2 | pages = 71–5 | date = June 2014 | pmid = 24446896 | doi = 10.3109/13506129.2013.876984 | pmc = 4021035 }}</ref> | Enfuvirtide<ref name="Sipe 2016">{{cite journal | vauthors = Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, Westermark P | title = Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines | journal = Amyloid | volume = 23 | issue = 4 | pages = 209–213 | date = December 2016 | pmid = 27884064 | doi = 10.1080/13506129.2016.1257986 | doi-access = free }}</ref> |- | Cystic fibrosis<ref name="Meng X 2017">{{cite journal | vauthors = Meng X, Clews J, Kargas V, Wang X, Ford RC | title = The cystic fibrosis transmembrane conductance regulator (CFTR) and its stability | journal = Cellular and Molecular Life Sciences | volume = 74 | issue = 1 | pages = 23–38 | date = January 2017 | pmid = 27734094 | doi = 10.1007/s00018-016-2386-8 | pmc=5209436}}</ref> | Cystic fibrosis transmembrane conductance regulator (CFTR) protein |- | Sickle cell disease<ref name="Stuart">{{cite journal | vauthors = Stuart MJ, Nagel RL | title = Sickle-cell disease | journal = Lancet | volume = 364 | issue = 9442 | pages = 1343–60 | year = 2004 | pmid = 15474138 | doi = 10.1016/S0140-6736(04)17192-4 | s2cid = 8139305 }}</ref> | Hemoglobin |- | Plasma cell dyscrasias (monoclonal gammopathies) | Gamma globulin |- | Exfoliation syndrome<ref name="Bernstein AM 2018">{{cite journal | vauthors = Bernstein AM, Ritch R, Wolosin JM | title = Exfoliation syndrome: A disease of autophagy and LOXL1 proteopathy | journal = Journal of Glaucoma | volume = 27 | issue = Supplement 1 | pages = S44–S53 | date = July 2018 | pmid = 29547474 | doi = 10.1097/IJG.0000000000000919 | pmc=6028293}}</ref> aka pseudoexfoliation syndrome | Aggregated fibrillar material (esp. LOXL1) |}

==Management==

The development of effective treatments for many proteopathies has been challenging.<ref name="Pepys 2006">{{cite journal | vauthors = Pepys MB | title = Amyloidosis | journal = Annu Rev Med | volume = 57 | pages = 223–241 | date = 2006 | pmid = 16409147 | doi = 10.1146/annurev.med.57.121304.131243}}</ref><ref name="Holtzman 2011">{{cite journal | vauthors = Holtzman DM, Morris JC, Goate AM | title = Alzheimer's disease: the challenge of the second century | journal = Sci Transl Med | volume = 3 | issue = 77 | year = 2011 | pmid = 21471435 | doi = 10.1126/scitranslmed.3002369 | pmc=3130546 | page=77sr1}}</ref> Because the proteopathies often involve different proteins arising from different sources, treatment strategies must be customized to each disorder; however, general therapeutic approaches include maintaining the function of affected organs, reducing the formation of the disease-causing proteins, preventing the proteins from misfolding and/or aggregating, or promoting their removal.<ref name="Pepys 2001">{{cite journal | vauthors = Pepys MB | title = Pathogenesis, diagnosis and treatment of systemic amyloidosis | journal = Phil Trans R Soc Lond B | volume = 356 | pages = 203–211 | date = 2001 | issue = 1406 | pmid = 11260801 | doi = 10.1098/rstb.2000.0766 | pmc=1088426}}</ref><ref name="Pepys 2006"/><ref name="Walker and LeVine 2002">{{cite journal | vauthors = Walker LC, LeVine H 3rd | title = Proteopathy: the next therapeutic frontier? | journal = Curr Opin Investig Drugs | volume = 3 | issue = 5 | year = 2002 | pmid = 12090553 | pages=782–7}}</ref> For example, in Alzheimer's disease, researchers are seeking ways to reduce the production of the disease-associated protein Aβ by inhibiting the enzymes that free it from its parent protein.<ref name="Holtzman 2011"/> Another strategy is to use antibodies to neutralize specific proteins by active or passive immunization.<ref name="Braczynski 2017">{{cite journal | vauthors = Braczynski AK, Schulz JB, Bach JP | title = Vaccination strategies in tauopathies and synucleinopathies | journal = J Neurochem | volume = 143 | issue = 5 | pages=467–488 | year = 2017 | pmid = 28869766 | doi = 10.1111/jnc.14207| doi-access = free }}</ref> In some proteopathies, inhibiting the toxic effects of protein oligomers might be beneficial.<ref name="Klein 2013">{{cite journal | vauthors = Klein WL | title = Synaptotoxic amyloid-β oligomers: a molecular basis for the cause, diagnosis, and treatment of Alzheimer's disease? | journal = J Alzheimers Dis | volume = 33 | issue = Suppl 1 | pages = S49-65 | date = 2013 | pmid = 22785404 | doi = 10.3233/JAD-2012-129039}}</ref>

For example, Amyloid A (AA) amyloidosis can be reduced by treating the inflammatory state that increases the amount of the protein in the blood (referred to as serum amyloid A, or SAA).<ref name="Pepys 2006" /> In immunoglobulin light chain amyloidosis (AL amyloidosis), chemotherapy can be used to lower the number of the blood cells that make the light chain protein that forms amyloid in various bodily organs.<ref name="Badar 2018">{{cite journal | vauthors = Badar T, D'Souza A, Hari P | title = Recent advances in understanding and treating immunoglobulin light chain amyloidosis | journal = F1000Res | year = 2018 | pmid = 30228867 | doi = 10.12688/f1000research.15353.1 | volume=7 | pmc=6117860 | page=1348 | doi-access = free }}</ref> Transthyretin (TTR) amyloidosis (ATTR) results from the deposition of misfolded TTR in multiple organs.<ref name="Carvalho 2015">{{cite journal | vauthors = Carvalho A, Rocha A, Lobato L | title = Liver transplantation in transthyretin amyloidosis: issues and challenges | journal = Liver Transpl | volume = 21 | issue = 3 | pages = 282–292 | date = 2015 | pmid = 25482846 | doi = 10.1002/lt.24058| doi-access = free }}</ref> Because TTR is mainly produced in the liver, TTR amyloidosis can be slowed in some hereditary cases by liver transplantation.<ref name="Suhr 2000">{{cite journal | vauthors = Suhr OB, Herlenius G, Friman S, Ericzon BG | title = Liver transplantation for hereditary transthyretin amyloidosis | journal = Liver Transpl | volume = 6 | issue = 3 | pages = 263–276 | date = 2000 | pmid = 10827225 | doi = 10.1053/lv.2000.6145| doi-access = free }}</ref> TTR amyloidosis also can be treated by stabilizing the normal assemblies of the protein (called tetramers because they consist of four TTR molecules bound together). Stabilization prevents individual TTR molecules from escaping, misfolding, and aggregating into amyloid.<ref name="Suhr 2016">{{cite journal | vauthors = Suhr OB, Larsson M, Ericzon BG, Wilczek HE et al | title = Survival After Transplantation in Patients With Mutations Other Than Val30Met: Extracts From the FAP World Transplant Registry | journal = Transplantation | volume = 100 | issue = 2 | pages = 373–381 | date = 2016 | pmid = 26656838 | doi = 10.1097/TP.0000000000001021 | pmc=4732012}}</ref><ref name="Coelho 2016">{{cite journal | vauthors = Coelho T et al | title = Mechanism of Action and Clinical Application of Tafamidis in Hereditary Transthyretin Amyloidosis | journal = Neurol Ther | volume = 5 | issue = 1 | pages = 1–25 | date = 2016 | pmid = 26894299 | doi = 10.1007/s40120-016-0040-x | pmc=4919130}}</ref>

Several other treatment strategies for proteopathies are being investigated, including small molecules and biologic medicines such as small interfering RNAs, antisense oligonucleotides, peptides, and engineered immune cells.<ref name="Suhr 2016"/><ref name="Badar 2018"/><ref name="Yu D 2012">{{cite journal | vauthors = Yu D et al | title = Single-stranded RNAs use RNAi to potently and allele-selectively inhibit mutant huntingtin expression | journal = Cell | volume = 150 | issue = 5 | pages = 895–908 | date = 2012 | pmid = 22939619 | doi = 10.1016/j.cell.2012.08.002 | pmc=3444165}}</ref><ref name="Nuvolone 2017">{{cite journal | vauthors = Nuvolone M, Merlini G | title = Emerging therapeutic targets currently under investigation for the treatment of systemic amyloidosis | journal = Expert Opin Ther Targets | volume = 21 | issue = 12 | pages = 1095–1110 | date = 2017 | pmid = 29076382 | doi = 10.1080/14728222.2017.1398235| s2cid = 46766370 }}</ref> In some cases, multiple therapeutic agents may be combined to improve effectiveness.<ref name="Badar 2018"/><ref name="Joseph 2018">{{cite journal | vauthors = Joseph NS, Kaufman JL | title = Novel Approaches for the Management of AL Amyloidosis | journal = Curr Hematol Malig Rep | volume = 13 | issue = 3 | pages = 212–219 | date = 2018 | pmid = 29951831 | doi = 10.1007/s11899-018-0450-1| s2cid = 49475930 }}</ref>

==Additional images== <gallery> File:Tauopathy in Alzheimer's disease.jpg|Micrograph of tauopathy (brown) in a neuronal cell body (arrow) and process (arrowhead) in the cerebral cortex of a patient with Alzheimer's disease. Bar = 25 microns (0.025mm). </gallery>

== References == {{reflist|35em}}

== External links == * [http://www.emedicine.com/med/topic3377.htm Amyloidosis] * [http://www.emedicine.com/neuro/topic662.htm Prion-Related Diseases] * [https://books.google.com/books?id=JD5s5RkWb3AC Protein Misfolding Diseases Book]

Category:Protein folding Category:Neurological disorders Category:Pathology Category:Amyloidosis