Synucleinopathies (also called α-Synucleinopathies) are neurodegenerative diseases characterised by the abnormal accumulation of aggregates of alpha-synuclein protein in neurons, nerve fibres or glial cells.[1] There are three main types of synucleinopathy: Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA).[1] Other rare disorders, such as various neuroaxonal dystrophies, also have α-synuclein pathologies.[2] Additionally, autopsy studies have shown that around 6% of sporadic Alzheimer's Disease exhibit α-synuclein positive Lewy pathology, and are sub-classed as Alzheimer's Disease with Amygdalar Restricted Lewy Bodies (AD/ALB).[3][4][5][6][7]
Synucleinopathy
Other names
α-Synucleinopathies
Positive α-Synuclein staining of a Lewy body in a patient with Parkinson's disease.
Synucleinopathies can sometimes overlap with tauopathies, possibly because of interaction between the synuclein and tau proteins.[9]
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 (REM) sleep, and act out their dreams or have other abnormal movements or vocalizations.[10] Abnormal sleep behaviors may appear decades before any other symptoms, often as an early sign of a synucleinopathy.[11] On autopsy, 94 to 98% of individuals with polysomnography-confirmed RBD are found to have a synucleinopathy—most commonly DLB or PD.[10][12][13] Other symptoms of the specific synucleinopathy usually manifest within 15 years of the diagnosis of RBD,[14] but may emerge up to 50 years after RBD diagnosis.[10]
Alpha-synuclein deposits can affect the cardiac muscle and blood vessels.[15] Almost all people with synucleinopathies have cardiovascular dysfunction, although most are asymptomatic.[15]
From chewing to defecation, alpha-synuclein deposits affect every level of gastrointestinal function. Symptoms include upper gastrointestinal tract dysfunction such as delayed gastric emptying or lower gastrointestinal dysfunction, such as constipation and prolonged stool transit time.[15]
Persons with PD are typically less caught up in their visual hallucinations than those with DLB.[16] There is a lower incidence of tremor at rest in DLB than in PD, and signs of parkinsonism in DLB are more symmetrical.[11] In MSA, 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.[17] Urinary difficulties are one of the earliest symptoms with MSA, and are often severe.[15]
DNA damageedit
Alpha-synuclein modulates DNA repair processes, including the repair of DNA double-strand breaks by the non-homologous end joining pathway.[18] The DNA repair function of alpha-synuclein appears to be compromised in Lewy body inclusion bearing neurons, and this may trigger cell death. Study of synucleinopathy mouse models of Parkinson's disease indicates that alpha-synuclein pathogenesis is associated with increased DNA damage and activation of the DNA damage response.[19]
^Goedert M, Jakes R, Spillantini MG (2017). "The Synucleinopathies: Twenty Years On". J Parkinsons Dis. 7 (s1): S53–S71. doi:10.3233/JPD-179005. PMC5345650. PMID 28282814.
^Arai, Yasushi; Yamazaki, Mineo; Mori, Osamu; Muramatsu, Hiromi; Asano, Goro; Katayama, Yasuo (January 2001). "α-Synuclein-positive structures in cases with sporadic Alzheimer's disease: morphology and its relationship to tau aggregation". Brain Research. 888 (2): 287–296. doi:10.1016/S0006-8993(00)03082-1. PMID 11150486. S2CID 3044534.
^Nelson, Peter T; Abner, Erin L; Patel, Ela; Anderson, Sonya; Wilcock, Donna M; Kryscio, Richard J; Van Eldik, Linda J; Jicha, Gregory A; Gal, Zsombor; Nelson, Ruth S; Nelson, Bela G; Gal, Jozsef; Azam, Md. Tofial; Fardo, David W; Cykowski, Matthew D (1 January 2018). "The Amygdala as a Locus of Pathologic Misfolding in Neurodegenerative Diseases". Journal of Neuropathology & Experimental Neurology. 77 (1): 2–20. doi:10.1093/jnen/nlx099. PMC5901077. PMID 29186501.
^Hamilton, Ronald L. (5 April 2006). "Lewy Bodies in Alzheimer's Disease: A Neuropathological Review of 145 Cases Using α-Synuclein Immunohistochemistry". Brain Pathology. 10 (3): 378–384. doi:10.1111/j.1750-3639.2000.tb00269.x. PMC8098522. PMID 10885656.
^Toledo, Jon B.; Gopal, Pallavi; Raible, Kevin; Irwin, David J.; Brettschneider, Johannes; Sedor, Samantha; Waits, Kayla; Boluda, Susana; Grossman, Murray; Van Deerlin, Vivianna M.; Lee, Edward B.; Arnold, Steven E.; Duda, John E.; Hurtig, Howard; Lee, Virginia M.-Y.; Adler, Charles H.; Beach, Thomas G.; Trojanowski, John Q. (March 2016). "Pathological α-synuclein distribution in subjects with coincident Alzheimer's and Lewy body pathology". Acta Neuropathologica. 131 (3): 393–409. doi:10.1007/s00401-015-1526-9. PMC4754135. PMID 26721587.
^Uchikado, Hirotake; Lin, Wen-Lang; DeLucia, Michael W.; Dickson, Dennis W. (July 2006). "Alzheimer Disease With Amygdala Lewy Bodies: A Distinct Form of α-Synucleinopathy". Journal of Neuropathology and Experimental Neurology. 65 (7): 685–697. doi:10.1097/01.jnen.0000225908.90052.07. PMC5706655. PMID 16825955.
^Pezzoli S, Cagnin A, Bandmann O, Venneri A (July 2017). "Structural and Functional Neuroimaging of Visual Hallucinations in Lewy Body Disease: A Systematic Literature Review". Brain Sci (Review). 7 (12): 84. doi:10.3390/brainsci7070084. PMC5532597. PMID 28714891.
^Moussaud S, Jones DR, Moussaud-Lamodière EL, et al. (October 2014). "Alpha-synuclein and tau: teammates in neurodegeneration?". Mol Neurodegener. 9: 43. doi:10.1186/1750-1326-9-43. PMC4230508. PMID 25352339.
^ abcSt Louis EK, Boeve BF (November 2017). "REM sleep behavior disorder: Diagnosis, clinical implications, and future directions". Mayo Clin. Proc. (Review). 92 (11): 1723–36. doi:10.1016/j.mayocp.2017.09.007. PMC6095693. PMID 29101940.
^ abSt Louis EK, Boeve AR, Boeve BF (May 2017). "REM sleep behavior disorder in Parkinson's disease and other synucleinopathies". Mov. Disord. (Review). 32 (5): 645–58. doi:10.1002/mds.27018. PMID 28513079. S2CID 46881921.
^Gomperts SN (April 2016). "Lewy body dementias: Dementia with Lewy bodies and Parkinson disease dementia". Continuum (Minneap Minn) (Review). 22 (2 Dementia): 435–63. doi:10.1212/CON.0000000000000309. PMC5390937. PMID 27042903.
^Schaser AJ, Osterberg VR, Dent SE, Stackhouse TL, Wakeham CM, Boutros SW, Weston LJ, Owen N, Weissman TA, Luna E, Raber J, Luk KC, McCullough AK, Woltjer RL, Unni VK (Jul 2019). "Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders". Sci. Rep. 9 (1): 10919. Bibcode:2019NatSR...910919S. doi:10.1038/s41598-019-47227-z. PMC6662836. PMID 31358782.
^Milanese C, Cerri S, Ulusoy A, Gornati SV, Plat A, Gabriels S, Blandini F, Di Monte DA, Hoeijmakers JH, Mastroberardino PG (Jul 2018). "Activation of the DNA damage response in vivo in synucleinopathy models of Parkinson's disease". Cell Death Dis. 9 (8): 818. doi:10.1038/s41419-018-0848-7. PMC6062587. PMID 30050065.