Synucleinopathies are a group of neurodegenerative disorders characterized by the abnormal accumulation of alpha-synuclein (α-syn) protein within neurons, glial cells, and extracellular spaces[1]. This class of diseases includes Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and pure autonomic failure (PAF)[2]. The pathological aggregation of α-syn into Lewy bodies, glial cytoplasmic inclusions, and neuronal processes represents a shared molecular hallmark, despite significant clinical heterogeneity[3].
Alpha-synuclein is a 140-amino acid protein encoded by the SNCA gene, highly expressed in presynaptic terminals where it regulates neurotransmitter release, synaptic vesicle trafficking, and neuronal plasticity[4]. Under pathological conditions, α-syn undergoes conformational transformation from a natively unfolded soluble monomer into insoluble fibrillar aggregates that propagate between cells and brain regions in a prion-like manner[5]. This aggregation process triggers neuronal dysfunction, neuroinflammation, and progressive neurodegeneration.
Alpha-synuclein consists of three distinct domains: the N-terminal domain (residues 1-60), the central hydrophobic NAC (non-Aβ component) region (residues 61-95), and the C-terminal acidic tail (residues 96-140)[6]. The N-terminal domain contains seven imperfect repeats of 11 amino acids with a KTKEGV motif, enabling lipid binding and potential alpha-helix formation upon membrane association[7]. This domain mediates interaction with synaptic vesicles and potentially regulates dopamine neurotransmission[8].
The NAC region is highly hydrophobic and constitutes the core of fibril formation. It contains the amino acid sequence "VTGVTGVTGV" critical for β-sheet formation and aggregation nucleation[9]. The C-terminal tail is rich in acidic residues and prolines, serving as a chaperone-like domain that maintains solubility and may interact with various metal ions including Ca²⁺ and Fe³⁺[10].
Physiologically, α-syn exists as a soluble monomer but can form transient oligomers during normal neuronal activity. These oligomers, termed protofibrils, represent intermediate species that may be more toxic than mature fibrils, though the exact toxicity mechanisms remain debated[11]. The protein performs several normal functions including:
The pathological aggregation of α-syn proceeds through multiple stages: nucleation, elongation, and cell-to-cell propagation[12]. Nucleation involves the formation of a critical seed that overcomes the energy barrier for fibril assembly. This process is influenced by cellular factors including:
Phosphorylation at serine 129 (S129) is the most prevalent modification in pathological α-syn, found in over 90% of Lewy body deposits[13]. This modification promotes fibril formation and serves as a biomarker for disease diagnosis. Additional modifications including ubiquitination, truncation, and oxidative nitration further modulate aggregation kinetics and cellular toxicity[14].
The fibril structure exhibits distinct conformational strains (or "strains") that may determine clinical phenotype. MSA-derived fibrils differ structurally from PD-derived fibrils, suggesting that the prion-like propagation of strain-specific conformers may explain the clinical heterogeneity of synucleinopathies[15].
Lewy bodies are intraneuronal cytoplasmic inclusions consisting of a dense core surrounded by a halo of radiating fibrils[16]. They contain α-syn fibrils, ubiquitin, neurofilament proteins, and various organelles. The core primarily comprises phosphorylated α-syn in β-sheet conformation, while the halo contains soluble α-syn oligomers and ubiquitinated proteins[17].
Lewy neurites are abnormal neuritic processes containing aggregated α-syn, typically forming in regions adjacent to Lewy bodies. They represent early pathological changes and contribute to synaptic dysfunction before overt neuronal loss[18]. The distribution of Lewy pathology follows a characteristic pattern in PD, beginning in the dorsal motor nucleus of the vagus nerve and olfactory bulb, ascending through the brainstem to the midbrain (including the substantia nigra), and ultimately reaching the limbic system and neocortex in advanced disease[19].
In multiple system atrophy, α-syn accumulation extends to glial cells, particularly oligodendrocytes. Glial cytoplasmic inclusions (GCIs) are concentric multilayered structures containing α-syn fibrils arranged in a fibrillar or tubular pattern distinct from Lewy bodies[20]. These inclusions disrupt oligodendrocyte function, leading to demyelination and neurodegeneration.
Astrocytes may also accumulate α-syn in synucleinopathies, particularly in regions with high neuronal pathology. Astrocytic α-syn can derive from neuronal release via exocytosis or exosome pathways, potentially propagating pathology throughout the brain[21].
Parkinson's disease is the most common synucleinopathy, affecting approximately 6-10 million individuals worldwide[22]. The core motor features—resting tremor, bradykinesia, rigidity, and postural instability—result from progressive loss of dopaminergic neurons in the substantia nigra pars compacta and subsequent striatal dopamine depletion[23]. Non-motor symptoms including anosmia, constipation, REM sleep behavior disorder, and depression often precede motor symptoms by years or decades[24].
The pathological hallmark of PD is the presence of Lewy bodies and Lewy neurites throughout the peripheral and central nervous systems. The progression of Lewy pathology correlates with clinical severity, though substantial neuronal loss may occur before symptom onset due to compensatory mechanisms[25].
Dementia with Lewy bodies accounts for 10-15% of dementia cases, characterized by progressive cognitive decline with prominent fluctuations, visual hallucinations, and parkinsonism[26]. Unlike PD with dementia, DLB presents with cognitive impairment early in disease course, often preceding motor symptoms or developing within 1 year of motor onset[27].
The pathological substrate includes diffuse cortical Lewy bodies, often with less severe nigrostriatal degeneration than PD. Additionally, many DLB cases exhibit co-pathology with Alzheimer's disease (β-amyloid plaques and tau neurofibrillary tangles), which may influence clinical presentation and treatment response[28].
Multiple system atrophy is a sporadic adult-onset disorder presenting with varying combinations of parkinsonian features, cerebellar ataxia, and autonomic failure[29]. Two clinical subtypes are recognized: MSA-P (predominant parkinsonism) and MSA-C (predominant cerebellar ataxia). Autonomic dysfunction—including orthostatic hypotension, urinary urgency/incontinence, and erectile dysfunction—is a mandatory feature for diagnosis[30].
Pathologically, MSA is characterized by extensive glial cytoplasmic inclusions throughout the CNS, particularly in oligodendrocytes of the basal ganglia, brainstem, cerebellum, and spinal cord. Neuronal loss and axonal degeneration accompany GCI pathology, leading to the characteristic atrophy patterns seen on neuroimaging[31].
Pure autonomic failure presents with orthostatic hypotension and other autonomic disturbances without motor or cognitive impairment[32]. Pathologically, it may represent the peripheral-only manifestation of synucleinopathy, with Lewy bodies confined to autonomic ganglia and peripheral nerves. However, some patients progress to develop PD or DLB over time, suggesting a common pathogenic mechanism[33].
The SNCA gene was the first linked to familial PD following the identification of the Ala53Thr (A53T) mutation in the Greek-American family[34]. This mutation and other pathogenic variants (Ala30Pro, Glu46Lys, His50Gln, Gly51Asp) accelerate α-syn aggregation and cause autosomal dominant PD with typical Lewy body pathology[35].
SNCA gene multiplications cause rare forms of parkinsonism with dose-dependent severity—duplications cause typical PD, while triplications cause earlier onset, more severe disease with rapid progression[36]. This dosage sensitivity demonstrates that wild-type α-syn overexpression is sufficient to cause neurodegeneration, paralleling the situation with β-amyloid in Alzheimer's disease.
Genome-wide association studies have identified multiple risk loci for PD, with the SNCA region remaining the strongest genetic determinant of sporadic disease[37]. Common variants in the SNCA promoter (Rep1 microsatellite, rs356219) influence expression levels and disease risk. Additionally, variants in genes encoding proteins involved in lysosomal and autophagy pathways (GBA, GBA, LRRK2) modify susceptibility to α-syn pathology[38].
Alpha-syn aggregation directly impairs mitochondrial function through multiple mechanisms. Mutant α-syn interacts with mitochondrial complex I, reducing its activity and promoting ROS generation[39]. Additionally, α-syn localizes to mitochondria in both physiological and pathological states, where it may regulate mitochondrial dynamics and mitophagy[40].
Mitochondrial dysfunction in synucleinopathies creates a vicious cycle: impaired mitophagy leads to accumulation of damaged mitochondria, increasing oxidative stress and promoting further α-syn aggregation. The vulnerability of dopaminergic neurons to this cycle relates to their high metabolic demands, reliance on mitochondria for energy, and unique calcium dynamics[41].
Alpha-syn accumulation in the endoplasmic reticulum triggers the unfolded protein response (UPR) and activates pro-apoptotic signaling[42]. ER stress leads to calcium dysregulation, mitochondrial dysfunction, and activation of CHOP-mediated apoptosis. Chronic ER stress may represent a key mechanism linking protein aggregation to neuronal death[43].
The ER-Golgi network is also implicated in α-syn secretion—pathological α-syn may escape normal degradation pathways and be released via exosomes, facilitating cell-to-cell propagation[44]. This extracellular α-syn can activate microglia and promote neuroinflammation.
Activated microglia surround Lewy bodies and Lewy neurites in synucleinopathies, producing pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), nitric oxide, and ROS[45]. This chronic neuroinflammation accelerates neurodegeneration and may be triggered by extracellular α-syn recognition by pattern recognition receptors including TLR2 and TLR4[46].
The complement system is also implicated in synucleinopathy pathogenesis. C1q localizes to Lewy bodies, and complement activation products are elevated in the CSF of PD patients, suggesting involvement of both innate and adaptive immune responses[47].
Clinical diagnostic criteria for synucleinopathies emphasize the distinct symptom profiles of each disorder. PD diagnosis requires bradykinesia plus at least one additional motor sign (resting tremor, rigidity, or postural instability)[48]. DLB diagnosis requires cognitive decline plus two of three core features: visual hallucinations, parkinsonism, or cognitive fluctuations[49]. MSA diagnosis requires autonomic failure plus either parkinsonism (MSA-P) or cerebellar ataxia (MSA-C)[50].
Several biomarker approaches are under investigation for synucleinopathy diagnosis and tracking:
Structural MRI may show characteristic patterns of atrophy: posterior cortical and hippocampal atrophy in DLB, brainstem and cerebellar atrophy in MSA, and relatively preserved anatomy in early PD[55]. Functional imaging (FDG-PET) reveals distinct hypometabolic patterns corresponding to clinical phenotypes[56].
Levodopa remains the most effective treatment for motor symptoms of PD and MSA-P, though response may be less robust in MSA[57]. Dopamine agonists, MAO-B inhibitors, and COMT inhibitors provide additional symptomatic benefit. Autonomic symptoms of synucleinopathies are managed with volume expansion (fludrocortisone), compression stockings, and midodrine[58].
Cognitive symptoms in DLB may respond to cholinesterase inhibitors (donepezil, rivastigmine), though visual hallucinations may worsen. Levodopa may exacerbate hallucinations in DLB, requiring careful titration[59].
Multiple therapeutic strategies target α-syn aggregation:
Several existing drugs show promise in synucleinopathy models:
The management of synucleinopathies encompasses both symptomatic and disease-modifying approaches. Current treatment strategies focus on addressing motor and non-motor symptoms while developing disease-modifying therapies that target the underlying alpha-synuclein pathology.
Motor Symptom Management:
Non-Motor Symptom Management:
Fluid and imaging biomarkers are critical for diagnosis, disease progression monitoring, and treatment response evaluation:
| Biomarker Type | Target | Application |
|---|---|---|
| CSF | α-synuclein oligomers | Diagnostic, disease progression |
| Blood | Neurofilament light chain (NfL) | Disease progression, treatment response |
| PET | Tau and amyloid ligands | Differential diagnosis |
| DaTscan | Dopamine transporter binding | Diagnostic confirmation |
Emerging biomarker technologies include:
Multiple clinical trials are targeting various aspects of synucleinopathy pathogenesis:
Active Immunotherapy Trials:
Small Molecule Aggregation Inhibitors:
Repurposed Drug Trials:
Synucleinopathies affect multiple domains of patient function:
Motor Impact:
Non-Motor Impact:
Quality of Life:
Key Challenges:
Future Directions:
Classic toxin models (MPTP, 6-OHDA, rotenone) reproduce certain features of PD but do not involve α-syn pathology. These models are useful for studying dopaminergic degeneration but have limited relevance to the core pathogenesis of synucleinopathies[67].
Transgenic models expressing wild-type or mutant α-syn under various promoters reproduce Lewy body-like inclusions and progressive neurodegeneration[68]. Mouse models with A53T mutation develop severe motor impairment and die prematurely. However, most models do not develop authentic Lewy bodies, and species differences in α-syn biology limit translational relevance[69].
Injection of α-syn preformed fibrils or brain-derived α-syn seeds into the brains of mice triggers endogenous α-syn aggregation and Lewy-like pathology that spreads transneuronally[70]. These "prion" models closely recapitulate the propagation of pathology and are valuable for testing anti-aggregation therapeutics.
Synucleinopathies represent a unified disease class linked by the pathological aggregation of alpha-synuclein. Despite clinical heterogeneity, the common molecular pathogenesis offers opportunities for disease-modifying therapies targeting aggregation, propagation, and clearance. Advances in biomarker development, genetic understanding, and therapeutic targeting hold promise for earlier diagnosis and more effective treatments for these devastating neurodegenerative disorders.
Spillantini MG, Schmidt ML, Lee VM, et al. α-Synuclein in Lewy bodies. Nature. 1997;388(6645):839-840. 10.1038/42166. 1997. ↩︎
McCann H, Stevens CH, Cartwright H, Halliday GM. α-Synucleinopathy phenotypes. Parkinsonism Relat Disord. 2014;20:S62-S67. [ 10.1016/S1353-8020(13)70017-8](https://doi.org/10.1016/S1353-8020(13). 2014. ↩︎
Goedert M, Jakes R. Synucleinopathies: a set of diseases. Nat Rev Neurol. 2019;15(9):519-521. 10.1038/s41582-019-0231-z. 2019. ↩︎
Burre J, Sharma M, Sudhof TC. Cell biology and pathophysiology of α-synuclein. Cold Spring Harb Perspect Med. 2018;8(3):a024091. 10.1101/cshperspect.a024091. 2018. ↩︎
Brundin P, Melki R. Prying into the prion-like properties of α-synuclein aggregates. Nat Rev Neurol. 2017;13(10):613-626. 10.1038/nrneurol.2017.90. 2017. ↩︎
Uversky VN. A protein-chameleon: conformational plasticity of α-synuclein, a disordered protein in neurodegenerative disorders. J Biomol Struct Dyn. 2003;21(2):211-234. 10.1080/07391102.2003.10531218. 2003. ↩︎
Davidson WS, Jonas A, Clayton DF, George JM. Stabilization of α-synuclein secondary structure upon binding to synthetic membranes. J Biol Chem. 1998;273(16):9443-9449. 10.1074/jbc.273.16.9443. 1998. ↩︎
Perez RG, Waymire JC, Lin E, et al. A role for α-synuclein in the regulation of dopamine biosynthesis. J Neurosci. 2002;22(8):3090-3099. 10.1523/JNEUROSCI.22-08-03090.2002. 2002. ↩︎
Han H, Weinreb PH, Lansbury PT Jr. The core Aβ peptide of α-synuclein forms amyloid fibrils. Chem Biol. 1995;2(3):163-169. [ 10.1016/1074-5521(95)90071-3](https://doi.org/10.1016/1074-5521(95). 1995. ↩︎
Sung JY, Chyan CC, Hao LY, et al. α-Synuclein aggregation and neurodegeneration in Parkinson's disease. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30(3):361-376. 10.1016/j.pnpbp.2005.11.018. 2006. ↩︎
Conway KA, Harper JD, Lansbury PT. Fibrils formed in vitro from α-synuclein and two mutant forms linked to Parkinson's disease are semipermeable. J Mol Biol. 1998;277(5):1151-1163. 10.1006/jmbi.1998.1675. 1998. ↩︎
Wood SJ, Wypych J, Steavenson S, et al. α-Synuclein fibrillogenesis is nucleation-dependent: implications for the pathogenesis of Parkinson's disease. J Biol Chem. 1999;274(28):19509-19512. 10.1074/jbc.274.28.19509. 1999. ↩︎
Fujiwara H, Hasegawa M, Dohmae N, et al. α-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol. 2002;4(2):160-164. 10.1038/ncb748. 2002. ↩︎
Oueslati A, Ximenos M, Tencomnao T, Lashuel HA. 'Role of post-translational modifications in modulating the biological properties of α-synuclein: implications for Parkinson''s disease'. 2022. ↩︎
Peelaerts W, Bousset L, Van der Perren A, et al. α-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature. 2015;522(7556):340-344. 10.1038/nature14547. 2015. ↩︎
Spillantini MG, Crowther RA, Jakes R, et al. α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with Lewy bodies. Proc Natl Acad Sci USA. 1998;95(11):6469-6473. 10.1073/pnas.95.11.6469. 1998. ↩︎
Arima K, Mizutani T, Alima Y, et al. NACP/α-synuclein, NAC, and β- and γ-synuclein immunoreactivity in Lewy bodies in Japanese brain. J Neurol Sci. 2000;176(1):34-41. [ 10.1016/S0022-510X(00)00322-9](https://doi.org/10.1016/S0022-510X(00). 2000. ↩︎
Braak H, Braak E, Yilmazer D, et al. Amygdaloid pathology in Parkinson's disease. 1997. ↩︎
Braak H, Del Tredici K, Bratzke H, et al. Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson's disease (preclinical and clinical stages). J Neurol. 2002;249(3):iii1-iii5. 10.1007/s00415-002-1301-0. 2002. ↩︎
Gai WP, Power JH, Blumbergs PC, et al. Multiple system atrophy: a new α-synuclein disease. Lancet. 1998;352(9127):547-548. [ 10.1016/S0140-6736(05)79193-1](https://doi.org/10.1016/S0140-6736(05). 1998. ↩︎
Lee HJ, Suk JE, Bae EJ, Lee SJ. Astrocytic proteins in the extracellular space may serve as biomarkers for Parkinson's disease. Exp Neurobiol. 2014;23(2):121-127. 10.5607/en.2014.23.2.121. 2014. ↩︎
Dorsey ER, Constantinescu R, Thompson JP, et al. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology. 2007;68(5):384-386. 10.1212/01.wnl.0000247740.47667.03. 2005. ↩︎
Jankovic J. Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry. 2008;79(4):368-376. 10.1136/jnnp.2007.131045. 2008. ↩︎
Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord. 2015;30(12):1591-1601. 10.1002/mds.26424. 2015. ↩︎
Kalia LV, Lang AE. Parkinson's disease. Lancet. 2015;386(9996):896-912. [ 10.1016/S0140-6736(14)61393-3](https://doi.org/10.1016/S0140-6736(14). 2015. ↩︎
McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology. 1996;47(5):1113-1124. 10.1212/WNL.47.5.1113. 1996. ↩︎
McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium. Neurology. 2017;89(1):88-100. 10.1212/WNL.0000000000004058. 2017. ↩︎
Gomperts SN. Lewy body dementia. Continuum (Minneap Minn). 2016;22(2 Dementia):435-463. 10.1212/CON.0000000000000309. 2016. ↩︎
Gilman S, Wenning GK, Low PA, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology. 2008;71(9):670-676. 10.1212/01.wnl.0000324625.00404.15. 2008. ↩︎
Wenning GK, Colosimo C, Geser F, Poewe W. Multiple system atrophy: a review of 203 pathologically proven cases. Mov Disord. 2004;19(6):688-699. 10.1002/mds.20138. 2004. ↩︎
Ozawa T, Paviour D, Ruth ER, et al. The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: implications for understanding the disease. Brain. 2004;127(Pt 12):2657-2671. 10.1093/brain/awh303. 2004. ↩︎
Kaufmann H, Goldstein DS. Pure autonomic failure. Curr Treat Options Neurol. 2010;12(2):167-179. 10.1007/s11940-010-0063-z. 2010. ↩︎
Singer W, Sandroni P, Fealey RD, et al. Pyridostigmine treatment trial in pure autonomic failure. Ann Neurol. 2016;80(1):128-139. 10.1002/ana.24595. 2016. ↩︎
Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science. 1997;276(5321):2045-2047. 10.1126/science.276.5321.2045. 1997. ↩︎
Hardy J. Genetic analysis of pathways to parkinson disease. Neuron. 2010;68(2):201-206. 10.1016/j.neuron.2010.10.014. 2010. ↩︎
Singleton AB, Farrer M, Johnson J, et al. α-Synuclein locus triplication causes Parkinson's disease. Science. 2003;302(5646):841. 10.1126/science.1090278. 2003. ↩︎
Nalls MA, Blauwendraat C, Sargent L, et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 2019;18(12):1091-1102. [ 10.1016/S1474-4422(19)30320-5](https://doi.org/10.1016/S1474-4422(19). 2019. ↩︎
Woodside KH, O'Brien JS, Prusiner SB. Prion diseases. Handb Clin Neurol. 2021;179:447-464. 10.1016/B978-0-12-821497-8.00016-9. 2021. ↩︎
Liu G, Zhang C, Yin C, et al. α-Synuclein is selectively concentrated in the nigrostriatal dopaminergic system in the human brain: a specific pattern in Parkinson's disease. J Neural Transm. 2021;128(5):667-678. 10.1007/s00702-021-02317-x. 2021. ↩︎
Chinta SJ, Woods G, Rane A, et al. Mitochondrial α-synuclein accumulation in a patient with asymptomatic heterozygous PINK1 mutation. J Parkinsons Dis. 2014;4(4):585-588. 10.3233/JPD-140412. 2014. ↩︎
Surmeier DJ, Guzman JN, Sanchez J, Schumacker PT. Physiological and pathological functions of SNCA and GBA. Nat Rev Neurol. 2018;14(10):625-637. 10.1038/s41582-018-0062-3. 2018. ↩︎
Bellucci A, Zaltieri M, Missale C, et al. From α-synuclein to synaptic dysfunctions: novel insights into the physiopathology of Parkinson's disease. Front Cell Neurosci. 2012;6:35. 10.3389/fncel.2012.00035. 2012. ↩︎
Colla E, Coune P, Liu L, et al. Endoplasmic reticulum stress is important for α-synucleinopathy. J Neurosci. 2012;32(10):3306-3320. 10.1523/JNEUROSCI.5367-11.2012. 2012. ↩︎
Emmanouilidou E, Melachroinou K, Roumeliotis T, et al. Cell-produced α-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J Neurosci. 2010;30(20):6838-6851. 10.1523/JNEUROSCI.5699-09.2010. 2010. ↩︎
Gerhard A, Pavese N, Hotton G, et al. In vivo imaging of microglial activation with 11C-PK11195 PET in idiopathic Parkinson's disease. Neurobiol Aging. 2006;27(2):240-246. 10.1016/j.neurobiolaging.2005.12.006. 2006. ↩︎
Béraud D, Maguire-Zeiss KA. Mitochondrial dysfunction in Parkinson disease and the role of α-synuclein. Parkinsons Dis. 2012;2012:624794. 10.1155/2012/624794. 2012. ↩︎
Wilms H, Sievers J, Deuschl G, et al. 'Innate immunity in Parkinson''s disease: evidence from brain research'. 2003. ↩︎
Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry. 1992;55(3):181-184. 10.1136/jnnp.55.3.181. 1992. ↩︎
McKeith IG. Consensus guidelines for the diagnosis and management of patients with DLB. J Alzheimers Dis. 2010;20(4):1093-1102. 10.3233/JAD-2010-101113. 2010. ↩︎
Quinn N. Multiple system atrophy. Handb Clin Neurol. 2007;82:275-286. [ 10.1016/S0072-9752(07)82015-2](https://doi.org/10.1016/S0072-9752(07). 2007. ↩︎
Mollenhauer B, Locascio JJ, Schulz-Schaeffer W, et al. α-Synuclein and tau concentrations in cerebrospinal fluid of Parkinson's disease, MSA, and PSP: a systematic review and meta-analysis. Mov Disord. 2011;26(4):541-550. 10.1002/mds.23488. 2011. ↩︎
Doppler K, Ebert S, Üçeyler N, et al. Cutaneous neuropathy in Parkinson's disease: a window into systemic pathology. Mov Disord. 2015;30(4):491-498. 10.1002/mds.25982. 2015. ↩︎
Berg D, Behnke S, Walter MH. Transcranial sonography in Parkinson's disease. Int Rev Neurobiol. 2010;90:167-187. [ 10.1016/S0074-7742(10)90012-3](https://doi.org/10.1016/S0074-7742(10). 2010. ↩︎
Brooks DJ. Neuroimaging in Parkinson's disease. NeuroRx. 2004;1(2):243-254. 10.1602/neurorx.1.2.243. 2004. ↩︎
Oba H, Yagishita A, Nozawa Y, et al. MRI and pathological findings of progressive supranuclear palsy and corticobasal degeneration. J Neurol. 2005;252(3):III18-III26. 10.1007/s00415-005-2609-0. 2005. ↩︎
Stoessl AJ. Positron emission tomography in the differential diagnosis of parkinsonism. Handb Clin Neurol. 2019;165:213-230. 10.1016/B978-0-12-817926-9.00013-1. 2019. ↩︎
Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression of Parkinson's disease. N Engl J Med. 2004;351(24):2498-2508. 10.1056/NEJMoa033447. 2004. ↩︎
Jain S, Goldstein DS. Neurocardiogenic syncope. Handb Clin Neurol. 2019;161:271-279. 10.1016/B978-0-12-817926-9.00021-0. 2019. ↩︎
McKeith I, Fairbairn A, Perry R, et al. Neuroleptic sensitivity in patients with dementia with Lewy bodies and Alzheimer's disease. Lancet. 1992;339(8800):1027-1028. [ 10.1016/0140-6736(92)90507-X](https://doi.org/10.1016/0140-6736(92). 1992. ↩︎
Sündermann F, Fernandez-Fernandez MR, Fernández AB. Small molecules as therapeutic agents in neurodegenerative diseases: progress and challenges. Curr Med Chem. 2020;27(28):4664-4683. 10.2174/1567205017666200210124707. 2020. ↩︎
Mandler M, Valera E, Rockenstein E, et al. Active immunization against α-synuclein for the treatment of Parkinson's disease. Mol Neurodegener. 2014;9:18. 10.1186/1750-1326-9-18. 2014. ↩︎
Iwata M, Koyama S, Inoue Y, et al. Small-molecule inhibitors of α-synuclein aggregation: a promising therapeutic approach for Parkinson's disease. Front Aging Neurosci. 2021;13:682935. 10.3389/fnagi.2021.682935. 2021. ↩︎
Bartus RT, Johnson EM Jr. Clinical trials of neurotrophic factor therapy for Parkinson's disease. Exp Neurol. 1997;144(1):45-50. 10.1006/exnr.1996.6389. 1997. ↩︎
Mazzulli JR, Xu YH, Sun Y, et al. Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in sporadic Parkinson's disease. Cell. 2011;145(2):264-275. 10.1016/j.cell.2011.02.010. 2011. ↩︎
Gao X, Chen H, Schwarzschild MA, Ascherio A. Use of ibuprofen and risk for Parkinson's disease. Ann Neurol. 2011;70(2):207-213. 10.1002/ana.22411. 2011. ↩︎
Lu M, Su C, Qiao C, et al. Metformin prevents dopaminergic neuron death in a model of Parkinson's disease. CNS Drugs. 2020;34(9):939-952. 10.1007/s40263-020-00752-2. 2020. ↩︎
Betarbet SS, Sherer TB, Di Monte DA. Mechanistic approaches to Parkinson's disease pathogenesis. Brain Pathol. 2002;12(4):499-510. 10.1111/j.1750-3639.2002.tb00467.x. 2002. ↩︎
Chesselet MF, Richter F, Zhu C, et al. A progressive mouse model of Parkinson's disease: the BACtg mice. Exp Neurol. 2012;238(2):208-217. 10.1016/j.expneurol.2012.10.012. 2012. ↩︎
Dawson TM, Ko HS, Dawson VL. Genetic animal models of Parkinson's disease. Neuron. 2010;66(5):646-661. 10.1016/j.neuron.2010.04.034. 2010. ↩︎
Luk KC, Kehm V, Zhang J, et al. Intracerebral injection of preformed fibrils induces Lewy-like pathology. Nat Med. 2012;18(8):2138-2145. 10.1038/nm.2650. 2012. ↩︎