# Huntingtin > Mediated Wiki article. Canonical URL: https://mediated.wiki/source/Huntingtin > Markdown URL: https://mediated.wiki/source/Huntingtin.md > Source: https://en.wikipedia.org/wiki/Huntingtin > Source revision: 1339236186 > License: Creative Commons Attribution-ShareAlike 4.0 International (https://creativecommons.org/licenses/by-sa/4.0/) {{short description|Gene and protein involved in Huntington's disease}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox gene}} '''Huntingtin''' ('''Htt''') is a human [protein](/source/protein) encoded by the ''HTT'' [gene](/source/gene), also known as ''IT15'' ("interesting transcript 15").{{cite journal | vauthors = ((Huntington's Disease Collaborative Research Group)) | title = A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group | journal = Cell | volume = 72 | issue = 6 | pages = 971–983 | date = Mar 1993 | pmid = 8458085 | doi = 10.1016/0092-8674(93)90585-E | hdl = 2027.42/30901 | s2cid = 802885 | hdl-access = free }} Pathogenic expansions in ''HTT'' (disease-causing repeat length increases) cause [Huntington's disease](/source/Huntington's_disease) (HD), and the protein has also been implicated in mechanisms of [long-term memory](/source/long-term_memory) storage.{{cite journal | vauthors = Choi YB, Kadakkuzha BM, Liu XA, Akhmedov K, Kandel ER, Puthanveettil SV | title = Huntingtin is critical both pre- and postsynaptically for long-term learning-related synaptic plasticity in Aplysia | journal = PLOS ONE | volume = 9 | issue = 7 | article-number = e103004 | date = July 23, 2014 | pmid = 25054562 | pmc = 4108396 | doi = 10.1371/journal.pone.0103004 | bibcode = 2014PLoSO...9j3004C | doi-access = free }} ''HTT'' is expressed in many tissues, with the highest levels in the brain. Expression is [developmentally](/source/Ontogeny) regulated and required for [embryogenesis](/source/embryogenesis).{{cite journal | vauthors = Nasir J, Floresco SB, O'Kusky JR, Diewert VM, Richman JM, Zeisler J, Borowski A, Marth JD, Phillips AG, Hayden MR | title = Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes | journal = Cell | volume = 81 | issue = 5 | pages = 811–823 | date = Jun 1995 | pmid = 7774020 | doi = 10.1016/0092-8674(95)90542-1 | s2cid = 16835259 | doi-access = free }} Huntingtin normally consists of 3,144 amino acids and has a predicted mass of ~350 [kDa](/source/atomic_mass_unit), depending on the length of its [polyglutamine tract](/source/polyglutamine_tract). Polymorphisms in ''HTT'' alter the number of [glutamine](/source/glutamine) residues: the [wild-type](/source/wild-type) allele encodes 6–35 repeats, whereas pathogenic expansions in HD exceed 36, with severe juvenile cases reaching ~250 repeats.{{cite journal | vauthors = Nance MA, Mathias-Hagen V, Breningstall G, Wick MJ, McGlennen RC | title = Analysis of a very large trinucleotide repeat in a patient with juvenile Huntington's disease | journal = Neurology | volume = 52 | issue = 2 | pages = 392–394 | date = Jan 1999 | pmid = 9932964 | doi = 10.1212/wnl.52.2.392 | s2cid = 33091017 }} The name ''huntingtin'' reflects this association with disease; ''IT15'' was its earlier designation. The molecular functions of huntingtin are not fully defined, but the protein is essential for [neuronal](/source/neuron) survival and development. It is thought to contribute to intracellular signaling pathways, [axonal transport](/source/axonal_transport), and [vesicle trafficking](/source/vesicle_trafficking), as well as to mediate protein–protein interactions. Huntingtin has also been shown to exert protective effects against [apoptosis](/source/apoptosis). Experimental disruption of ''HTT'' in model organisms results in embryonic lethality, underscoring its critical role in development. Expanded polyglutamine tracts in huntingtin cause toxic gain-of-function effects leading to [Huntington's disease](/source/Huntington's_disease), an [autosomal dominant](/source/autosomal_dominant) [neurodegenerative disease](/source/neurodegenerative_disease). The pathogenic protein aggregates in neurons, disrupting cellular processes and ultimately causing cell death. == Gene == The [5'-end (five prime end)](/source/Directionality_(molecular_biology)) of the ''HTT'' gene has a sequence of three DNA bases, cytosine-adenine-guanine (CAG), coding for the amino acid [glutamine](/source/glutamine), that is repeated multiple times. This region is called a [trinucleotide repeat](/source/trinucleotide_repeat). The usual CAG repeat count is between seven and 35 repeats. The ''HTT'' gene is located on the short arm (p) of [chromosome 4](/source/chromosome_4_(human)) at position 16.3, from [base pair](/source/base_pair) 3,074,510 to base pair 3,243,960.{{Cite web |title=HTT gene |url=https://medlineplus.gov/genetics/gene/htt/ |access-date=2016-02-18 |archive-date=2016-02-02 |archive-url=https://web.archive.org/web/20160202113623/http://ghr.nlm.nih.gov/gene/HTT |url-status=live}} == Structure == The Huntingtin (HTT) protein is a large, predominantly α-helical molecule composed of 3,144 amino acids and weighing approximately 348kDa in its canonical form. Its structure is organized into three major domains: the [amino-terminal](/source/amino-terminal) domain, the [carboxy-terminal](/source/carboxy-terminal) domain, and a smaller bridge domain that connects the two. Both the amino- and carboxy-terminal regions are characterized by multiple [HEAT repeat](/source/HEAT_repeat)s (named for Huntingtin, Elongation factor 3, Protein phosphatase 2A, and lipid kinase TOR), which are arranged in a [solenoid](/source/solenoid) or superhelical fashion and play a crucial role in mediating protein-protein interactions. The bridge domain contains various types of tandem repeats and helps maintain the structural connection between the larger domains. The highly variable N-terminal segment of huntingtin contains the [polyglutamine](/source/polyglutamine_tract) (polyQ) tract—expanded in Huntington's disease—which is often intrinsically disordered and not fully resolved in high-resolution structures. Huntingtin's flexible, extended architecture is stabilized when complexed with [HAP40](/source/HAP40), a partner protein, allowing the protein to function as a scaffold and interaction hub in the cell.{{cite journal | vauthors = Truant R, Harding RJ, Neuman K, Maiuri T | title = Revisiting huntingtin activity and localization signals in the context of protein structure | journal = Journal of Huntington's Disease | volume = 13 | issue = 4 | pages = 419–430 | date = November 2024 | pmid = 39973382 | doi = 10.1177/18796397241295303}} In recent years, multiple research groups have managed to resolve the 3D structure of full-size HTT using cryogenic electron microscopy [cryoEM](/source/cryoEM). This revealed the 3D architecture of the various helical [HEAT repeat](/source/HEAT_repeat) domains that make up the protein's native fold, as illustrated in the figure to right.{{cite journal | vauthors = Guo Q, Huang B, Cheng J, Seefelder M, Engler T, Pfeifer G, Oeckl P, Otto M, Moser F, Maurer M, Pautsch A, Baumeister W, Fernandez-Busnadiego R, Kochanek S | title = The cryo-electron microscopy structure of huntingtin. | journal = Nature | volume = 555 | issue = 7694 | pages = 117–120 | date = Mar 2018 | pmid = 29466333 | pmc = 5837020 | doi = 10.1038/nature25502 | bibcode = 2018Natur.555..117G | doi-access = free}} However, up to 25% of the protein chain was not visible in the structure, due to flexibility. This notably included the N-terminal region affected by mutations in Huntington's disease, as discussed below. == Function == The function of huntingtin (Htt) is not well understood but it is involved in [axonal transport](/source/axonal_transport).{{cite journal | vauthors = Vitet H, Brandt V, Saudou F | title = Traffic signaling: new functions of huntingtin and axonal transport in neurological disease | journal = Current Opinion in Neurobiology | volume = 63 | pages = 122–130 | date = August 2020 | pmid = 32408142 | doi = 10.1016/j.conb.2020.04.001 | s2cid = 218596089}} Huntingtin is essential for development, and its absence is lethal in mice. The protein has no [sequence homology](/source/sequence_homology) with other proteins and is highly expressed in neurons and testes in humans and rodents.{{cite journal | vauthors = Cattaneo E, Zuccato C, Tartari M | title = Normal huntingtin function: an alternative approach to Huntington's disease | journal = Nature Reviews. Neuroscience | volume = 6 | issue = 12 | pages = 919–930 | date = December 2005 | pmid = 16288298 | doi = 10.1038/nrn1806 | s2cid = 10119487 }} Huntingtin upregulates the expression of [brain-derived neurotrophic factor](/source/brain-derived_neurotrophic_factor) (BDNF) at the transcription level, but the mechanism by which huntingtin regulates gene expression has not been determined.{{cite journal | vauthors = Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, MacDonald ME, Friedlander RM, Silani V, Hayden MR, Timmusk T, Sipione S, Cattaneo E | title = Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease | journal = Science | location = New York, N.Y. | volume = 293 | issue = 5529 | pages = 493–498 | date = July 2001 | pmid = 11408619 | doi = 10.1126/science.1059581 | s2cid = 20703272 }} From [immunohistochemistry](/source/immunohistochemistry), [electron microscopy](/source/electron_microscopy), and [subcellular fractionation](/source/subcellular_fractionation) studies of the molecule, it has been found that huntingtin is primarily associated with [vesicle](/source/vesicle_(biology))s and [microtubules](/source/microtubules).{{cite journal | vauthors = Hoffner G, Kahlem P, Djian P | title = Perinuclear localization of huntingtin as a consequence of its binding to microtubules through an interaction with beta-tubulin: relevance to Huntington's disease | journal = Journal of Cell Science | volume = 115 | issue = Pt 5 | pages = 941–948 | date = March 2002 | pmid = 11870213 | doi = 10.1242/jcs.115.5.941}}{{cite journal | vauthors = DiFiglia M, Sapp E, Chase K, Schwarz C, Meloni A, Young C, Martin E, Vonsattel JP, Carraway R, Reeves SA | title = Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons | journal = Neuron | volume = 14 | issue = 5 | pages = 1075–1081 | date = May 1995 | pmid = 7748555 | doi = 10.1016/0896-6273(95)90346-1 | s2cid = 18071283 | doi-access = free}} These appear to indicate a functional role in cytoskeletal anchoring or transport of [mitochondria](/source/mitochondria). The Htt protein is involved in vesicle trafficking as it interacts with HIP1, a [clathrin](/source/clathrin)-binding protein, to mediate [endocytosis](/source/endocytosis), the trafficking of materials into a cell.{{cite journal | vauthors = Velier J, Kim M, Schwarz C, Kim TW, Sapp E, Chase K, Aronin N, DiFiglia M | title = Wild-type and mutant huntingtins function in vesicle trafficking in the secretory and endocytic pathways | journal = Experimental Neurology | volume = 152 | issue = 1 | pages = 34–40 | date = July 1998 | pmid = 9682010 | doi = 10.1006/exnr.1998.6832 | s2cid = 36726422 }}{{cite journal | vauthors = Waelter S, Scherzinger E, Hasenbank R, Nordhoff E, Lurz R, Goehler H, Gauss C, Sathasivam K, Bates GP, Lehrach H, Wanker EE | title = The huntingtin interacting protein HIP1 is a clathrin and alpha-adaptin-binding protein involved in receptor-mediated endocytosis | journal = Human Molecular Genetics | volume = 10 | issue = 17 | pages = 1807–1817 | date = August 2001 | pmid = 11532990 | doi = 10.1093/hmg/10.17.1807 | doi-access = free }} Huntingtin has also been shown to have a role in the establishment in [epithelial polarity](/source/epithelial_polarity) through its interaction with [RAB11A](/source/RAB11A).{{cite journal | vauthors = Elias S, McGuire JR, Yu H, Humbert S | title = Huntingtin Is Required for Epithelial Polarity through RAB11A-Mediated Apical Trafficking of PAR3-aPKC | journal = PLOS Biology | volume = 13 | issue = 5 | article-number = e1002142 | date = May 2015 | pmid = 25942483 | pmc = 4420272 | doi = 10.1371/journal.pbio.1002142 | doi-access = free }} === Interactions === Huntingtin has been found to interact directly with at least 19 other [proteins](/source/proteins), of which six are used for transcription, four for transport, three for cell signalling, and six others of unknown function (HIP5, HIP11, HIP13, HIP15, HIP16, and CGI-125).{{cite journal | vauthors = Harjes P, Wanker EE | title = The hunt for huntingtin function: interaction partners tell many different stories | journal = Trends in Biochemical Sciences | volume = 28 | issue = 8 | pages = 425–433 | date = Aug 2003 | pmid = 12932731 | doi = 10.1016/S0968-0004(03)00168-3 }} Over 100 interacting proteins have been found, such as [huntingtin-associated protein 1](/source/huntingtin-associated_protein_1) (HAP1) and [huntingtin interacting protein 1](/source/Hip-1) (HIP1), these were typically found using [two-hybrid screening](/source/two-hybrid_screening) and confirmed using [immunoprecipitation](/source/immunoprecipitation).{{cite journal | vauthors = Goehler H, Lalowski M, Stelzl U, Waelter S, Stroedicke M, Worm U, Droege A, Lindenberg KS, Knoblich M, Haenig C, Herbst M, Suopanki J, Scherzinger E, Abraham C, Bauer B, Hasenbank R, Fritzsche A, Ludewig AH, Büssow K, Buessow K, Coleman SH, Gutekunst CA, Landwehrmeyer BG, Lehrach H, Wanker EE | title = A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease | journal = Molecular Cell | volume = 15 | issue = 6 | pages = 853–865 | date = Sep 2004 | pmid = 15383276 | doi = 10.1016/j.molcel.2004.09.016 | author23-link = Bernhard Landwehrmeyer | doi-access = free }}{{cite journal | vauthors = Wanker EE, Rovira C, Scherzinger E, Hasenbank R, Wälter S, Tait D, Colicelli J, Lehrach H | title = HIP-I: a huntingtin interacting protein isolated by the yeast two-hybrid system | journal = Human Molecular Genetics | volume = 6 | issue = 3 | pages = 487–495 | date = Mar 1997 | pmid = 9147654 | doi = 10.1093/hmg/6.3.487 | doi-access = free }} {| class="wikitable" |- ! Interacting Protein ! PolyQ length dependence ! Function |- | α-adaptin C/[HYPJ](/source/AP2A2) | Yes | Endocytosis |- | [Akt](/source/AKT1)/PKB | No | Kinase |- | [CBP](/source/CREB_binding_protein) | Yes | Transcriptional co-activator with acetyltransferase activity |- | [CA150](/source/Transcription_elongation_regulator_1) | No | Transcriptional activator |- | [CIP4](/source/TRIP10) | Yes | cdc42-dependent signal transduction |- | [CtBP](/source/RBBP8) | Yes | Transcription factor |- | [FIP2](/source/Optineurin) | Not known | Cell morphogenesis |- | [Grb2](/source/Grb2){{cite journal | vauthors = Liu YF, Deth RC, Devys D | title = SH3 domain-dependent association of huntingtin with epidermal growth factor receptor signaling complexes | journal = The Journal of Biological Chemistry | volume = 272 | issue = 13 | pages = 8121–8124 | date = Mar 1997 | pmid = 9079622 | doi = 10.1074/jbc.272.13.8121 | doi-access = free }} | Not known | Growth factor receptor binding protein |- | [HAP1](/source/Huntingtin-associated_protein_1) | Yes | Membrane trafficking |- | HAP40 (''[F8A1](/source/F8A1)'', ''F8A2'', ''F8A3'') | Not known | Unknown |- | [HIP1](/source/Hip-1) | Yes | Endocytosis, proapoptotic |- | [HIP14](/source/ZDHHC17)/HYP-H | Yes | Trafficking, endocytosis |- | [N-CoR](/source/Nuclear_receptor_co-repressor_1) | Yes | Nuclear receptor co-repressor |- | [NF-κB](/source/NF-%CE%BAB) | Not known | Transcription factor |- | [p53](/source/p53){{cite journal | vauthors = Steffan JS, Kazantsev A, Spasic-Boskovic O, Greenwald M, Zhu YZ, Gohler H, Wanker EE, Bates GP, Housman DE, Thompson LM | title = The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 12 | pages = 6763–6768 | date = Jun 2000 | pmid = 10823891 | pmc = 18731 | doi = 10.1073/pnas.100110097 | bibcode = 2000PNAS...97.6763S | doi-access = free }} | No | Transcription factor |- | [PACSIN1](/source/PACSIN1){{cite journal | vauthors = Modregger J, DiProspero NA, Charles V, Tagle DA, Plomann M | title = PACSIN 1 interacts with huntingtin and is absent from synaptic varicosities in presymptomatic Huntington's disease brains | journal = Human Molecular Genetics | volume = 11 | issue = 21 | pages = 2547–2558 | date = Oct 2002 | pmid = 12354780 | doi = 10.1093/hmg/11.21.2547 | doi-access = free }} | Yes | Endocytosis, actin cytoskeleton |- | [DLG4](/source/DLG4) (PSD-95) | Yes | Postsynaptic Density 95 |- | [RASA1](/source/RASA1) (RasGAP) | Not known | Ras GTPase activating protein |- | [SH3GL3](/source/SH3GL3){{cite journal | vauthors = Sittler A, Wälter S, Wedemeyer N, Hasenbank R, Scherzinger E, Eickhoff H, Bates GP, Lehrach H, Wanker EE | title = SH3GL3 associates with the Huntingtin exon 1 protein and promotes the formation of polygln-containing protein aggregates | journal = Molecular Cell | volume = 2 | issue = 4 | pages = 427–436 | date = Oct 1998 | pmid = 9809064 | doi = 10.1016/S1097-2765(00)80142-2 | doi-access = free }} | Yes | Endocytosis |- | [SIN3A](/source/SIN3A) | Yes | Transcriptional repressor |- | [Sp1](/source/Sp1_transcription_factor){{cite journal | vauthors = Li SH, Cheng AL, Zhou H, Lam S, Rao M, Li H, Li XJ | title = Interaction of Huntington disease protein with transcriptional activator Sp1 | journal = Molecular and Cellular Biology | volume = 22 | issue = 5 | pages = 1277–1287 | date = Mar 2002 | pmid = 11839795 | pmc = 134707 | doi = 10.1128/MCB.22.5.1277-1287.2002 }} | Yes | Transcription factor |} Huntingtin has also been shown to [interact](/source/Protein-protein_interaction) with: {{div col|colwidth=20em}} * [UBE2K](/source/UBE2K),{{cite journal | vauthors = Kalchman MA, Graham RK, Xia G, Koide HB, Hodgson JG, Graham KC, Goldberg YP, Gietz RD, Pickart CM, Hayden MR | title = Huntingtin is ubiquitinated and interacts with a specific ubiquitin-conjugating enzyme | journal = The Journal of Biological Chemistry | volume = 271 | issue = 32 | pages = 19385–19394 | date = Aug 1996 | pmid = 8702625 | doi = 10.1074/jbc.271.32.19385 | doi-access = free }} * [MAP3K10](/source/MAP3K10),{{cite journal | vauthors = Liu YF, Dorow D, Marshall J | title = Activation of MLK2-mediated signaling cascades by polyglutamine-expanded huntingtin | journal = The Journal of Biological Chemistry | volume = 275 | issue = 25 | pages = 19035–19040 | date = Jun 2000 | pmid = 10801775 | doi = 10.1074/jbc.C000180200 | doi-access = free }} * [OPTN](/source/Optineurin),{{cite journal | vauthors = Hattula K, Peränen J | title = FIP-2, a coiled-coil protein, links Huntingtin to Rab8 and modulates cellular morphogenesis | journal = Current Biology | volume = 10 | issue = 24 | pages = 1603–1606 | year = 2000 | pmid = 11137014 | doi = 10.1016/S0960-9822(00)00864-2 | s2cid = 12836037 | doi-access = free | bibcode = 2000CBio...10.1603H }} * [PRPF40A](/source/PRPF40A), * [SETD2](/source/SETD2),{{cite journal | vauthors = Faber PW, Barnes GT, Srinidhi J, Chen J, Gusella JF, MacDonald ME | title = Huntingtin interacts with a family of WW domain proteins | journal = Human Molecular Genetics | volume = 7 | issue = 9 | pages = 1463–1474 | date = Sep 1998 | pmid = 9700202 | doi = 10.1093/hmg/7.9.1463 | doi-access = free }} * [TRIP10](/source/TRIP10),{{cite journal | vauthors = Holbert S, Dedeoglu A, Humbert S, Saudou F, Ferrante RJ, Néri C | title = Cdc42-interacting protein 4 binds to huntingtin: neuropathologic and biological evidence for a role in Huntington's disease | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 5 | pages = 2712–2717 | date = Mar 2003 | pmid = 12604778 | pmc = 151406 | doi = 10.1073/pnas.0437967100 | bibcode = 2003PNAS..100.2712H | doi-access = free }} * [ZDHHC17](/source/ZDHHC17).{{cite journal | vauthors = Singaraja RR, Hadano S, Metzler M, Givan S, Wellington CL, Warby S, Yanai A, Gutekunst CA, Leavitt BR, Yi H, Fichter K, Gan L, McCutcheon K, Chopra V, Michel J, Hersch SM, Ikeda JE, Hayden MR | title = HIP14, a novel ankyrin domain-containing protein, links huntingtin to intracellular trafficking and endocytosis | journal = Human Molecular Genetics | volume = 11 | issue = 23 | pages = 2815–2828 | date = Nov 2002 | pmid = 12393793 | doi = 10.1093/hmg/11.23.2815 | doi-access = free }} {{Div col end}} == Clinical significance == === Huntington's disease === {{main|Huntington's disease}} {| class="wikitable" border="1" style="float:right; margin-left:15px; text-align:center;" |+Classification of the trinucleotide repeat, and resulting disease status, depends on the number of CAG repeats |- ! Repeat count ! Classification ! Disease status |- | <26 | Normal | Unaffected |- | 27–35 | Intermediate | Unaffected |- | 36–40 | Reduced penetrance | +/- Affected |- | >40 | Full penetrance | Affected |} Huntington's disease (HD) is caused by a mutated form of the huntingtin gene, where excessive (more than 36) CAG repeats result in formation of an unstable protein.{{cite journal | vauthors = Walker FO | title = Huntington's disease | journal = Lancet | location = London, England | volume = 369 | issue = 9557 | pages = 218–228 | date = Jan 2007 | pmid = 17240289 | doi = 10.1016/S0140-6736(07)60111-1 | s2cid = 46151626}} These expanded repeats lead to production of a huntingtin protein that contains an abnormally long [polyglutamine tract](/source/polyglutamine_tract) at the N-terminus. This makes it part of a class of neurodegenerative disorders known as [trinucleotide repeat disorders](/source/trinucleotide_repeat_disorders) or polyglutamine disorders. The key sequence which is found in Huntington's disease is a trinucleotide repeat expansion of [glutamine](/source/glutamine) residues beginning at the 18th amino acid. In unaffected individuals, this contains between 9 and 35 glutamine residues with no adverse effects. However, 36 or more residues produce an erroneous mutant form of Htt, (mHtt). Reduced [penetrance](/source/penetrance) is found in counts 36–39.{{cite journal | vauthors = Chong SS, Almqvist E, Telenius H, LaTray L, Nichol K, Bourdelat-Parks B, Goldberg YP, Haddad BR, Richards F, Sillence D, Greenberg CR, Ives E, Van den Engh G, Hughes MR, Hayden MR | title = Contribution of DNA sequence and CAG size to mutation frequencies of intermediate alleles for Huntington disease: evidence from single sperm analyses | journal = Human Molecular Genetics | volume = 6 | issue = 2 | pages = 301–309 | date = Feb 1997 | pmid = 9063751 | doi = 10.1093/hmg/6.2.301 | doi-access = free}} N-terminal fragments of mHtt have been discovered in Huntington's disease patients. These fragments can be generated by protease enzymes that cut this elongated protein into fragments. Moreover, recent research has identified aberrant splicing to affect the mutant gene products, yielding fragments that coincide with the first exon of the protein.{{cite journal | vauthors = Sathasivam K, Neueder A, Gipson TA, Landles C, Benjamin AC, Bondulich MK, Smith DL, Faull RL, Roos RA, Howland D, Detloff PJ, Housman DE, Bates GP | title = Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 6 | pages = 2366–2370 | date = Feb 2013 | pmid = 23341618 | pmc = 3568346 | doi = 10.1073/pnas.1221891110 | bibcode = 2013PNAS..110.2366S | doi-access = free | hdl = 1721.1/79814 | hdl-access = free }} These protein fragments are observed to form abnormal clumps, known as neuronal intranuclear inclusions (NIIs), inside nerve cells, and may attract other, normal proteins into the clumps. The characteristic presence of these clumps in patients was thought to contribute to the development of Huntington disease.{{cite journal | vauthors = Davies SW, Turmaine M, Cozens BA, DiFiglia M, Sharp AH, Ross CA, Scherzinger E, Wanker EE, Mangiarini L, Bates GP | title = Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation | journal = Cell | volume = 90 | issue = 3 | pages = 537–548 | date = Aug 1997 | pmid = 9267033 | doi = 10.1016/S0092-8674(00)80513-9 | s2cid = 549691 | doi-access = free }} However, later research raised questions about the role of the inclusions (clumps) by showing the presence of visible NIIs extended the life of neurons and acted to reduce intracellular mutant huntingtin in neighboring neurons.{{cite journal | vauthors = Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S | title = Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death | journal = Nature | volume = 431 | issue = 7010 | pages = 805–810 | date = Oct 2004 | pmid = 15483602 | doi = 10.1038/nature02998 | bibcode = 2004Natur.431..805A | doi-access = free }} One confounding factor is that different types of aggregates are now recognised to be formed by the mutant protein, including protein deposits that are too small to be recognised as visible deposits in the above-mentioned studies.{{cite journal | vauthors = Sahl SJ, Lau L, Vonk WI, Weiss LE, Frydman J, Moerner WE | title = Delayed Emergence of Subdiffraction-Sized Mutant Huntingtin Fibrils Following Inclusion Body Formation | journal = Quarterly Reviews of Biophysics | volume = 49 | article-number = e2 | date = 2016 | pmid = 26350150 | pmc = 4785097 | doi = 10.1017/S0033583515000219 | doi-access = free }} The likelihood of neuronal death remains difficult to predict. Likely multiple factors are important, including: (1) the length of CAG repeats in the huntingtin gene and (2) the neuron's exposure to diffuse intracellular mutant huntingtin protein. NIIs (protein clumping) can be helpful as a coping mechanism—and not simply a pathogenic mechanism—to stem neuronal death by decreasing the amount of diffuse huntingtin.{{cite journal | vauthors = Orr HT | title = Neurodegenerative disease: neuron protection agency | journal = Nature | volume = 431 | issue = 7010 | pages = 747–748 | date = Oct 2004 | pmid = 15483586 | doi = 10.1038/431747a | bibcode = 2004Natur.431..747O | s2cid = 285829 }} This process is particularly likely to occur in the [striatum](/source/striatum) (a part of the brain that coordinates movement) primarily, and the [frontal cortex](/source/frontal_cortex) (a part of the brain that controls thinking and emotions). Further, it is possible the pathogenic mechanism lay more with the RNA transcripts and their potential CAG repeats to exhibit RNAi than with the actual huntingtin protein itself.{{cite journal | vauthors = Murmann AE, Patel M, Jeong SY, Bartom ET, Jennifer Morton A, Peter ME | title = The length of uninterrupted CAG repeats in stem regions of repeat disease associated hairpins determines the amount of short CAG oligonucleotides that are toxic to cells through RNA interference | journal = Cell Death & Disease | volume = 13 | issue = 12 | article-number = 1078 | date = 2022 | pmid = 36585400 | pmc = 9803637 | doi = 10.1038/s41419-022-05494-1 }} People with 36 to 40 CAG repeats may or may not develop the signs and symptoms of Huntington disease, while people with more than 40 repeats will develop the disorder during a normal lifetime. When there are more than 60 CAG repeats, the person develops a severe form of HD known as [juvenile HD](/source/Juvenile_Huntington's_disease). Therefore, the number of CAG (the sequence coding for the amino acid glutamine) repeats influences the age of onset of the disease. No case of HD has been diagnosed with a count less than 36. As the altered gene is passed from one generation to the next, the size of the CAG repeat expansion can change; it often increases in size, especially when it is inherited from the father. People with 28 to 35 CAG repeats have not been reported to develop the disorder, but their children are at risk of having the disease if the repeat expansion increases. In the pathogenesis of the disease, there is further somatic expansion of CAG repeats. It takes decades to reach 80 repeats, then years to reach 150 repeats. Beyond 150, cellular toxicity start to manifest. Over months, the neuron slowly loses its cell identity until cell death pathways are activated.{{cite journal | vauthors = Handsaker RE, Kashin S, Reed NM, Tan S, Lee WS, McDonald TM, Morris K, Kamitaki N, Mullally CD, Morakabati NR, Goldman M, Lind G, Kohli R, Lawton E, Hogan M, Ichihara K, Berretta S, McCarroll SA | title = Long somatic DNA-repeat expansion drives neurodegeneration in Huntington's disease | journal = Cell | volume = 188 | issue = 3 | pages = 623–639.e19 | date = February 2025 | pmid = 39824182 | pmc = 11822645 | doi = 10.1016/j.cell.2024.11.038 | doi-access = free }} {{Clear}} === Mitochondrial dysfunction === Huntingtin is a [scaffolding protein](/source/scaffolding_protein) in the [ATM](/source/ATM_serine%2Fthreonine_kinase) oxidative DNA damage response complex. Mutant huntingtin (mHtt) plays a key role in [mitochondrial dysfunction](/source/mitochondrial_dysfunction) involving the inhibition of [mitochondrial electron transport](/source/Electron_transport_chain), inhibition of mitochondrial import processes, higher levels of [reactive oxygen species](/source/reactive_oxygen_species) and increased [oxidative stress](/source/oxidative_stress).{{cite journal | vauthors = Liu Z, Zhou T, Ziegler AC, Dimitrion P, Zuo L | title = Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications | journal = Oxidative Medicine and Cellular Longevity | volume = 2017 | article-number = 2525967 | date = 2017 | pmid = 28785371 | pmc = 5529664 | doi = 10.1155/2017/2525967 | doi-access = free }}{{cite journal | vauthors = Maiuri T, Mocle AJ, Hung CL, Xia J, van Roon-Mom WM, Truant R | title = Huntingtin is a scaffolding protein in the ATM oxidative DNA damage response complex | journal = Human Molecular Genetics | volume = 26 | issue = 2 | pages = 395–406 | date = 25 December 2016 | pmid = 28017939 | doi = 10.1093/hmg/ddw395 | doi-access = free }} The promotion of [oxidative damage to DNA](/source/DNA_oxidation) may contribute to [Huntington's disease](/source/Huntington's_disease) pathology.{{cite journal | vauthors = Ayala-Peña S | title = Role of oxidative DNA damage in mitochondrial dysfunction and Huntington's disease pathogenesis | journal = Free Radical Biology & Medicine | volume = 62 | pages = 102–110 | date = September 2013 | pmid = 23602907 | pmc = 3722255 | doi = 10.1016/j.freeradbiomed.2013.04.017 }} == See also == * [Votoplam](/source/Votoplam) == References == {{Reflist|35em}} == Further reading == {{refbegin|35em}} * {{cite journal | vauthors = Kosinski CM, Schlangen C, Gellerich FN, Gizatullina Z, Deschauer M, Schiefer J, Young AB, Landwehrmeyer GB, Toyka KV, Sellhaus B, Lindenberg KS | title = Myopathy as a first symptom of Huntington's disease in a Marathon runner | journal = Movement Disorders | volume = 22 | issue = 11 | pages = 1637–1640 | date = August 2007 | pmid = 17534945 | doi = 10.1002/mds.21550 | s2cid = 30904037 }} * {{cite journal | vauthors = Bates G | title = Huntingtin aggregation and toxicity in Huntington's disease | journal = Lancet | location = London, England | volume = 361 | issue = 9369 | pages = 1642–1644 | date = May 2003 | pmid = 12747895 | doi = 10.1016/S0140-6736(03)13304-1 | s2cid = 7587406 }} * {{cite journal | vauthors = Cattaneo E | title = Dysfunction of wild-type huntingtin in Huntington disease | journal = News in Physiological Sciences | volume = 18 | pages = 34–37 | date = Feb 2003 | pmid = 12531930 | doi = 10.1152/nips.01410.2002 }} * {{cite journal | vauthors = Gárdián G, Vécsei L | title = Huntington's disease: pathomechanism and therapeutic perspectives | journal = Journal of Neural Transmission | location = Vienna, Austria | volume = 111 | issue = 10–11 | pages = 1485–1494 | date = Oct 2004 | pmid = 15480847 | doi = 10.1007/s00702-004-0201-4 | s2cid = 2961376 }} * {{cite journal | vauthors = Landles C, Bates GP | title = Huntingtin and the molecular pathogenesis of Huntington's disease. Fourth in molecular medicine review series | journal = EMBO Reports | volume = 5 | issue = 10 | pages = 958–963 | date = Oct 2004 | pmid = 15459747 | pmc = 1299150 | doi = 10.1038/sj.embor.7400250 }} * {{cite journal | vauthors = Jones AL | title = The localization and interactions of huntingtin | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 354 | issue = 1386 | pages = 1021–1027 | date = Jun 1999 | pmid = 10434301 | pmc = 1692601 | doi = 10.1098/rstb.1999.0454 }} * {{cite journal | vauthors = Li SH, Li XJ | title = Huntingtin and its role in neuronal degeneration | journal = The Neuroscientist | volume = 10 | issue = 5 | pages = 467–475 | date = Oct 2004 | pmid = 15359012 | doi = 10.1177/1073858404266777 | s2cid = 19491573 }} * {{cite journal | vauthors = MacDonald ME, Novelletto A, Lin C, Tagle D, Barnes G, Bates G, Taylor S, Allitto B, Altherr M, Myers R | title = The Huntington's disease candidate region exhibits many different haplotypes | journal = Nature Genetics | volume = 1 | issue = 2 | pages = 99–103 | date = May 1992 | pmid = 1302016 | doi = 10.1038/ng0592-99 | s2cid = 25472459 }} * {{cite journal | vauthors = MacDonald ME | title = Huntingtin: alive and well and working in middle management | journal = Science's STKE | volume = 2003 | issue = 207 | article-number = pe48 | date = Nov 2003 | pmid = 14600292 | doi = 10.1126/stke.2003.207.pe48 | s2cid = 35318234 }} * {{cite journal | vauthors = Myers RH | title = Huntington's disease genetics | journal = NeuroRx | volume = 1 | issue = 2 | pages = 255–262 | date = Apr 2004 | pmid = 15717026 | pmc = 534940 | doi = 10.1602/neurorx.1.2.255 }} * {{cite journal | vauthors = Rangone H, Humbert S, Saudou F | title = Huntington's disease: how does huntingtin, an anti-apoptotic protein, become toxic? | journal = Pathologie-Biologie | volume = 52 | issue = 6 | pages = 338–342 | date = Jul 2004 | pmid = 15261377 | doi = 10.1016/j.patbio.2003.06.004 }} * {{cite journal | vauthors = Young AB | title = Huntingtin in health and disease | journal = The Journal of Clinical Investigation | volume = 111 | issue = 3 | pages = 299–302 | date = Feb 2003 | pmid = 12569151 | pmc = 151871 | doi = 10.1172/JCI17742 }} {{refend}} == External links == * {{MeshName|Huntingtin+protein,+human}} * [https://web.archive.org/web/20090327130709/http://www.stanford.edu/group/hopes/causes/huntprot/p1.html The Huntingtin Protein and Protein Aggregation] at [https://hopes.stanford.edu/ HOPES] {{Webarchive|url=https://web.archive.org/web/20210212014602/https://hopes.stanford.edu/ |date=2021-02-12 }}: Huntington's Outreach Project for Education at Stanford * [https://www.hda.org.uk/ The HDA] Huntington's Disease Association UK * {{OMIM|143100}} * {{EntrezGene|3064}} * [https://web.archive.org/web/19980211231514/http://bioinformatics.weizmann.ac.il/cards-bin/carddisp?HD GeneCard] * [https://web.archive.org/web/20120205103304/http://www.ihop-net.org/UniPub/iHOP/bng/88980.html iHOP] Category:Human proteins Category:Huntington's disease Category:Genes on human chromosome 4 --- Adapted from the Wikipedia article [Huntingtin](https://en.wikipedia.org/wiki/Huntingtin) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Huntingtin?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.