{{Infobox medical condition (new) | name = Synucleinopathy | synonym = α-synucleinopathies | image = Lewy Body alphaSynuclein.jpg | image_size = | field = neurology | symptoms = Autonomic dysfunction, motor impairments, cognitive and sleep issues, parkinsonism, memory loss, hallucinations | duration = Long term | causes = Unknown | types = Parkinson's disease, dementia with Lewy bodies, multiple system atrophy | caption = Positive α-synuclein staining (brown) of a Lewy body in the substantia nigra of an individual with Parkinson's disease }} '''Synucleinopathies''' are [[neurodegenerative]] diseases characterised by the abnormal accumulation of aggregates of [[alpha-synuclein|alpha-synuclein protein]] in neurons, nerve fibres or [[glia]]l cells.<ref name=Miglis2021>{{cite journal |vauthors=Miglis MG, Adler CH, Antelmi E, et al |title=Biomarkers of conversion to α-synucleinopathy in isolated rapid-eye-movement sleep behaviour disorder |journal=Lancet Neurol |volume=20 |issue=8 |pages=671–684 |date=August 2021 |pmid=34302789 |pmc=8600613 |doi=10.1016/S1474-4422(21)00176-9|type=Review}}</ref> The synucleinopathies include [[Parkinson's disease]] (PD), [[dementia with Lewy bodies]] (DLB), and [[multiple system atrophy]] (MSA).<ref name=Miglis2021/> Other rare disorders, such as various neuroaxonal dystrophies, also have α-synuclein pathologies.<ref name=Goedert2017>{{cite journal |vauthors=Goedert M, Jakes R, Spillantini MG |title=The Synucleinopathies: Twenty Years On |journal=J Parkinsons Dis |volume=7 |issue=s1 |pages=S53–S71 |date=2017 |pmid=28282814 |pmc=5345650 |doi=10.3233/JPD-179005 |type=Review}}</ref>
== Classification == The synucleinopathies include [[Parkinson's disease]] (PD), [[dementia with Lewy bodies]] (DLB), and [[multiple system atrophy]] (MSA).<ref name=Miglis2021/> Other rare disorders, such as various neuroaxonal dystrophies, also have α-synuclein pathologies.<ref name=Goedert2017/>
== Signs and symptoms == The synucleinopathies have shared features of [[parkinsonism]], impaired cognition, [[sleep disorder]]s, and [[visual hallucination]]s.<ref name=Pezzoli2017>{{cite journal |vauthors=Pezzoli S, Cagnin A, Bandmann O, Venneri A |title=Structural and Functional Neuroimaging of Visual Hallucinations in Lewy Body Disease: A Systematic Literature Review |journal=Brain Sci |volume=7 |issue=12 |page= 84|date=July 2017 |pmid=28714891 |pmc=5532597 |doi=10.3390/brainsci7070084 |type=Review|doi-access=free }}</ref>
Synucleinopathies can overlap with [[tauopathies]], possibly because of interaction between the synuclein and [[Tau protein|tau]] proteins.<ref>{{Cite journal |vauthors= Li W, Li JY |date=March 26, 2024|title=Overlaps and divergences between tauopathies and synucleinopathies: a duet of neurodegeneration |journal=Translational Neurodegeneration |volume=13 |issue=1 |page=16 |doi=10.1186/s40035-024-00407-y |doi-access=free |issn=2047-9158 |pmc=10964635 |pmid=38528629|type=Review}}</ref>
[[REM sleep behavior disorder]] (RBD) is a [[parasomnia]] in which individuals with RBD lose the paralysis of muscles (atonia) that is normal during [[rapid eye movement sleep|rapid eye movement (REM) sleep]], and act out their dreams or have other abnormal movements or vocalizations.<ref name=StLouisNov2017>{{cite journal |vauthors=St Louis EK, Boeve BF |title=REM sleep behavior disorder: Diagnosis, clinical implications, and future directions |journal=Mayo Clin. Proc. |volume=92 |issue=11 |pages=1723–1736 |date=November 2017 |pmid=29101940 |pmc=6095693 |doi=10.1016/j.mayocp.2017.09.007 |type=Review |url=http://www.mayoclinicproceedings.org/article/S0025-6196(17)30688-2/fulltext}}</ref> Abnormal sleep behaviors may appear decades before any other symptoms, often as an [[prodome|early sign]] of a synucleinopathy.<ref name=StLouisMay2017>{{cite journal |vauthors=St Louis EK, Boeve AR, Boeve BF |title=REM sleep behavior disorder in Parkinson's disease and other synucleinopathies |journal=Mov. Disord. |volume=32 |issue=5 |pages=645–658 |date=May 2017 |pmid=28513079 |doi=10.1002/mds.27018|s2cid=46881921 |type=Review }}</ref> On autopsy, 94 to 98% of individuals with [[polysomnography]]-confirmed RBD are found to have a synucleinopathy—most commonly DLB or PD.<ref name=StLouisNov2017/><ref name=Boot2013>{{cite journal |vauthors=Boot BP, McDade EM, McGinnis SM, Boeve BF |title=Treatment of dementia with Lewy bodies |journal=Curr Treat Options Neurol |volume=15 |issue=6 |pages=738–764 |date=December 2013 |pmid=24222315 |pmc=3913181 |doi=10.1007/s11940-013-0261-6 |type=Review}}</ref><ref name=Boot2015>{{cite journal |vauthors=Boot BP |title=Comprehensive treatment of dementia with Lewy bodies |journal=Alzheimers Res Ther |volume=7 |issue=1 |article-number=45 |date=2015 |pmid=26029267 |pmc=4448151 |doi=10.1186/s13195-015-0128-z |type=Review |doi-access=free }}</ref> Other symptoms of the specific synucleinopathy usually manifest within 15 years of the diagnosis of RBD,<ref name=Walker2015>{{cite journal |vauthors=Walker Z, Possin KL, Boeve BF, Aarsland D |title=Lewy body dementias |journal=Lancet |volume=386 |issue=10004 |pages=1683–1697 |date=October 2015 |pmid=26595642 |pmc=5792067 |doi=10.1016/S0140-6736(15)00462-6 |type=Review}}</ref> but may emerge up to 50 years after RBD diagnosis.<ref name=StLouisNov2017/>
Alpha-synuclein deposits can affect the [[myocard|cardiac muscle]] and blood vessels.<ref name=Palma2018/> Almost all people with synucleinopathies have cardiovascular dysfunction, although most are asymptomatic.<ref name=Palma2018>{{cite journal |vauthors=Palma JA, Kaufmann H |title=Treatment of autonomic dysfunction in Parkinson disease and other synucleinopathies |journal=Mov. Disord. |volume=33 |issue=3 |pages=372–390 |date=March 2018 |pmid=29508455 |pmc=5844369 |doi=10.1002/mds.27344 |type=Review}}</ref>
From chewing to [[defecation]], alpha-synuclein deposits affect every level of gastrointestinal function. Symptoms include upper [[gastrointestinal tract]] dysfunction such as [[Gastroparesis|delayed gastric emptying]] or lower gastrointestinal dysfunction, such as constipation and prolonged stool transit time.<ref name=Palma2018/>
[[Urinary retention]], [[nocturia|waking at night to urinate]], increased urinary frequency and urgency, and over- or underactive bladder are common in people with synucleinopathies.<ref name=Palma2018/> Sexual dysfunction usually appears early in synucleinopathies, and may include [[erectile dysfunction]], and difficulties achieving [[orgasm]] or [[ejaculation|ejaculating]].<ref name=Palma2018/>
== Mechanism == The [[pathology|pathological]] aggregation of alpha-synuclein plays a key role in neurodegenerative disease.<ref name=Arias2025>{{Cite journal |vauthors= Arias-Carrión O, Guerra-Crespo M, Padilla-Godínez FJ, Soto-Rojas LO, Manjarrez E |date=June 4, 2025 |title=α-Synuclein Pathology in Synucleinopathies: Mechanisms, Biomarkers, and Therapeutic Challenges |journal=International Journal of Molecular Sciences |language=en |volume=26 |issue=11 |page=5405 |doi=10.3390/ijms26115405 |doi-access=free |issn=1422-0067 |pmc=12155115 |pmid=40508212|type=Review}}</ref> The misfolding and aggregation of alpha-synuclein form [[Fibril|toxic fibrils]], which in turn form pathological inclusions, such as [[Lewy body|Lewy bodies]].<ref>{{Cite journal |vauthors=Negi S, Khurana N, Duggal N |date=July 2024|title=The misfolding mystery: α-synuclein and the pathogenesis of Parkinson's disease |url=https://www.sciencedirect.com/science/article/pii/S0197018624000871 |journal=Neurochemistry International |volume=177 |article-number=105760 |doi=10.1016/j.neuint.2024.105760 |issn=0197-0186|pmid=38723900|type=Review|url-access=subscription }}</ref> These protein deposits are a hallmark of synucleinopathies, and may interrupt crucial neuronal processes, such as functions of [[Synaptic vesicle|synaptic vesicles]], leading to neuronal death.<ref name=Arias2025/> While PD and DLB are characterized by neuronal aggregates of alpha-synuclein, MSA is characterized by glial aggregates, featuring glial cytoplasmic inclusions rather than Lewy bodies.<ref>{{cite journal |vauthors=Estaun-Panzano J, Arotcarena ML, Bezard E |title=Monitoring α-synuclein aggregation |journal=Neurobiol Dis |volume=176 |article-number=105966 |date=January 2023 |pmid=36527982 |pmc=9875312 |doi=10.1016/j.nbd.2022.105966 |type=Review}}</ref>
Alpha-synuclein is encoded by the ''SNCA'' [[gene]], and rare mutations in this gene can lead to dysfunctions of the [[protein structure]].<ref name="Yaribash2025">{{Cite journal |vauthors=Yaribash S, Mohammadi K, Sani MA |date=March 26, 2025|title=Alpha-Synuclein Pathophysiology in Neurodegenerative Disorders: A Review Focusing on Molecular Mechanisms and Treatment Advances in Parkinson's Disease |journal=Cellular and Molecular Neurobiology |language=en |volume=45 |issue=1 |article-number=30 |doi=10.1007/s10571-025-01544-2 |issn=1573-6830 |pmc=11947388 |pmid=40140103|type=Review}}</ref> [[Post-translational modification|Post-translational modifications]] are also implicated in the aggregation of alpha-synuclein, mostly occurring in the [[C-terminus]]. Phosphorylation, acetylation, ubiquitination, oxidation, and other modifications alter the structure and charge of alpha-synuclein, which can in turn lead to the formation of Lewy bodies.<ref name=Burré2018>{{Cite journal |vauthors=Burré J, Sharma M, Südhof TC|date=March 2018|title=Cell Biology and Pathophysiology of α-Synuclein |journal=Cold Spring Harbor Perspectives in Medicine |volume=8 |issue=3 |article-number=a024091 |doi=10.1101/cshperspect.a024091 |issn=2157-1422 |pmc=5519445 |pmid=28108534|type=Review}}</ref>
Alpha-synuclein has a [[Prion|prion-like]] molecular spread and is suggested to be released through rare [[exocytosis]] pathways.<ref name=Burré2018/> This release with [[Exosome (vesicle)|exosomes]] on their way to degradation in [[Lysosome|lysosomes]] suggests this process may be calcium-dependent, and therefore suggests propagation of misfolded alpha-synuclein between neurons synaptically connected.<ref name=Burré2018/> Neuronal death caused by aggregated alpha-synuclein may also further accelerate the formation of these toxic aggregates, which can then trigger a selective progression of neuronal death through impairment of the [[Mitochondrion|mitochondria]], alteration of [[Calcium metabolism|calcium homeostasis]], and lysosomal dysfunction.<ref name=Yaribash2025/><ref name=Calabresi2023>{{Cite journal |vauthors=Calabresi P, Mechelli A, Natale G, Volpicelli-Daley L, Di Lazzaro G, Ghiglieri V |date=March 2023|title=Alpha-synuclein in Parkinson's disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction |url=https://www.nature.com/articles/s41419-023-05672-9 |journal=Cell Death & Disease |language=en |volume=14 |issue=3 |page=176 |doi=10.1038/s41419-023-05672-9 |issn=2041-4889|pmid=36859484|type=Review|pmc=9977911 }}</ref>
Early synaptic and [[Neuroplasticity|plastic]] alterations mediated by alpha-synuclein, as well as the mechanisms of inflammation and synaptic dysfunction that occurs before [[neurodegeneration]], are of key interest for investigating possible therapies for synucleinpathies.<ref name=Calabresi2023/>
==Diagnosis== ===Differential diagnosis=== Persons with PD are typically less caught up in their visual hallucinations than those with DLB.<ref name=Burghaus2012>{{cite journal |vauthors=Burghaus L, Eggers C, Timmermann L, Fink GR, Diederich NJ |title=Hallucinations in neurodegenerative diseases |journal=CNS Neurosci Ther |volume=18 |issue=2 |pages=149–159 |date=February 2012 |pmid=21592320 |pmc=6493408 |doi=10.1111/j.1755-5949.2011.00247.x |type=Review }}</ref> There is a lower incidence of tremor at rest in DLB than in PD, and signs of parkinsonism in DLB are more symmetrical.<ref name=StLouisMay2017/> In MSA, [[dysautonomia|autonomic dysfunction]] appears earlier and is more severe, and is accompanied by uncoordinated movements, while visual hallucinations and fluctuating cognition are less common than in DLB.<ref name=Gomperts2016>{{cite journal |vauthors=Gomperts SN |title=Lewy body dementias: Dementia with Lewy bodies and Parkinson disease dementia |journal=Continuum (Minneap Minn) |volume=22 |issue=2 Dementia |pages=435–463 |date=April 2016 |pmid=27042903 |pmc=5390937 |doi=10.1212/CON.0000000000000309 |type=Review}}</ref> Urinary difficulties are one of the earliest symptoms with MSA, and are often severe.<ref name=Palma2018/>
== Management == As of 2016, there are no medications that stop or improve the progression of synucleinopathies; treatments are limited to managing symptoms.<ref name=Valera2016>{{cite journal |vauthors=Valera E, Monzio Compagnoni G, Masliah E |title=Review: Novel treatment strategies targeting alpha-synuclein in multiple system atrophy as a model of synucleinopathy |journal=Neuropathol Appl Neurobiol |volume=42 |issue=1 |pages=95–106 |date=February 2016 |pmid=26924723 |pmc=4785838 |doi=10.1111/nan.12312 |url=}}</ref> Symptomatic therapies include medications for motor symptoms, treatments for autonomic dysfunction, and management of sleep or cognitive problems.<ref name=Palma2018/> [[Non-pharmacological intervention|Non-pharmacological]] approaches such as [[physical therapy]], [[occupational therapy]], and [[Speech–language pathology|speech therapy]] are also commonly used.<ref name=Palma2018/><ref name=Palma2024>{{cite journal |vauthors=Palma JA, Thijs RD |title=Non-Pharmacological Treatment of Autonomic Dysfunction in Parkinson's Disease and Other Synucleinopathies |journal=J Parkinsons Dis |volume=14 |issue=s1 |pages=S81–S92 |date=2024 |pmid=37694308 |pmc=11380254 |doi=10.3233/JPD-230173 |url=}}</ref>
Since alpha-synuclein is involved in the synucleinopathies, many potential [[Disease-modifying treatment|disease-modifying treatments]] target this protein and its role in early inflammation and synaptic dysfunction.<ref name=Valera2016/>
==See also== * [[Proteopathy]] * [[Anti-α-synuclein drug]]
==References== {{reflist}}{{Central nervous system disease|state={{Central nervous system disease|state=collapsed}}}} [[Category:Lewy body dementia]] [[Category:Neurological disorders]]