The biological basis of the neurodegenerative movement disorder, Parkinson's disease (PD), is still unclear despite it being 'discovered' over 200 years ago in Western Medicine. Based on current PD knowledge, there are widely varying theories as to its pathobiology. The aim of this article was to explore some of these different theories by summarizing the viewpoints of laboratory and clinician scientists in the PD field, on the biological basis of the disease. To achieve this aim, we posed this question to thirteen "PD experts" from six continents (for global representation) and collated their personal opinions into this article. The views were varied, ranging from toxin exposure as a PD trigger, to LRRK2 as a potential root cause, to toxic alpha-synuclein being the most important etiological contributor. Notably, there was also growing recognition that the definition of PD as a single disease should be reconsidered, perhaps each with its own unique pathobiology and treatment regimen.

1st Department of Neurology and International Clinical Research Center St Anne's University Hospital and Faculty of Medicine Masaryk University Brno Czech Republic

Applied Neuroscience Research Group CEITEC Masaryk University Brno Czech Republic

Atlantic Senior Fellow for Equity in Brain Health at the Global Brain Health Institute Dublin Ireland

Centro de Biología Integrativa Facultad de Ciencias Universidad Mayor Santiago Chile

Centro FONDAP de Gerociencia Salud Mental y Metabolismo Santiago Chile

Departamento de Farmacologia Universidade Federal do Rio Grande do Sul Porto Alegre Brazil

Department of Internal Medicine Kilimanjaro Christian Medical Centre Moshi Tanzania

Department of Neurology Juntendo University School of Medicine 2 1 1 Hongo Bunkyo ku Tokyo 113 8421 Japan

Division of Molecular Biology and Human Genetics Department of Biomedical Sciences Faculty of Medicine and Health Sciences Stellenbosch University Cape Town South Africa

Division of Neurology Department of Medicine Faculty of Medicine University of Malaya Kuala Lumpur Malaysia

Faculty of Medicine Mansoura University Dakahleya Egypt

Griffith Institute of Drug Discovery Griffith University Brisbane QLD Australia

Institute of Global Health and Human Ecology New Cairo 11835 Egypt

Institute of Neurogenetics University of Lübeck and University Hospital Schleswig Holstein Lübeck Germany

Instituto de Neurociencia Biomédica Facultad de Medicina Universidad de Chile Santiago Chile

Neurodegenerative Disorders Collaborative Laboratory RIKEN Center for Brain Science 2 1 Hirosawa Wako Saitama 351 0106 Japan

Neuroscience Research Australia; Faculty of Medicine University of New South Wales; Kinghorn Centre for Clinical Genomics Garvan Institute of Medical Research Darlinghurst; Department of Neurology Prince of Wales Hospital South Eastern Sydney Local Health District Randwick NSW Australia

Norman Fixel Institute for Neurological Diseases McKnight Brain Institute University of Florida Gainesville FL USA

Pacific Parkinson's Research Centre Department of Medicine Djavad Mowafaghian Centre for Brain Health University of British Columbia Vancouver BC Canada

Research Institute of Disease of Old Age Graduate School of Medicine Juntendo University 2 1 1 Hongo Bunkyo ku Tokyo 113 8421 Japan

Serviço de Neurologia Hospital de Clínicas de Porto Alegre Porto Alegre Brazil

South African Medical Research Council Stellenbosch University Genomics of Brain Disorders Research Unit Stellenbosch University Cape Town South Africa

The Mah Pooi Soo and Tan Chin Nam Centre for Parkinson's and Related Disorders Faculty of Medicine University of Malaya Kuala Lumpur Malaysia

Zobrazit více v PubMed

Del Rey NL-G, et al. Advances in Parkinson’s disease: 200 years later. Front. Neuroanat. 2018;12:113. doi: 10.3389/fnana.2018.00113. PubMed DOI PMC

Cherian A, Divya KP. Genetics of Parkinson’s disease. Acta Neurol. Belg. 2020;120:1297–1305. doi: 10.1007/s13760-020-01473-5. PubMed DOI

Blauwendraat C, Nalls MA, Singleton AB. The genetic architecture of Parkinson’s disease. Lancet Neurol. 2020;19:170–178. doi: 10.1016/S1474-4422(19)30287-X. PubMed DOI PMC

San Luciano M, et al. Nonsteroidal anti-inflammatory use and LRRK2 Parkinson’s disease penetrance. Mov. Disord. J. Mov. Disord. Soc. 2020;35:1755–1764. doi: 10.1002/mds.28189. PubMed DOI PMC

Grünewald A, Kumar KR, Sue CM. New insights into the complex role of mitochondria in Parkinson’s disease. Prog. Neurobiol. 2019;177:73–93. doi: 10.1016/j.pneurobio.2018.09.003. PubMed DOI

Zaltieri M, et al. Mitochondrial dysfunction and α-synuclein synaptic pathology in Parkinson’s disease: who’s on first? Park. Dis. 2015;2015:108029. PubMed PMC

Ganjam GK, et al. Mitochondrial damage by α-synuclein causes cell death in human dopaminergic neurons. Cell Death Dis. 2019;10:865. doi: 10.1038/s41419-019-2091-2. PubMed DOI PMC

Zimprich A, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 2004;44:601–607. doi: 10.1016/j.neuron.2004.11.005. PubMed DOI

Paisán-Ruíz C, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron. 2004;44:595–600. doi: 10.1016/j.neuron.2004.10.023. PubMed DOI

Hulihan MM, et al. LRRK2 Gly2019Ser penetrance in Arab–Berber patients from Tunisia: a case-control genetic study. Lancet Neurol. 2008;7:591–594. doi: 10.1016/S1474-4422(08)70116-9. PubMed DOI

Aasly JO, et al. Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson’s disease: LRRK2 P.Asn1437His and Parkinson’s disease. Mov. Disord. 2010;25:2156–2163. doi: 10.1002/mds.23265. PubMed DOI PMC

Ross OA, et al. Lrrk2 and Lewy body disease. Ann. Neurol. 2006;59:388–393. doi: 10.1002/ana.20731. PubMed DOI

Goedert M, Spillantini MG, Del Tredici K, Braak H. 100 years of Lewy pathology. Nat. Rev. Neurol. 2013;9:13–24. doi: 10.1038/nrneurol.2012.242. PubMed DOI

Healy DG, et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol. 2008;7:583–590. doi: 10.1016/S1474-4422(08)70117-0. PubMed DOI PMC

Ross OA, et al. Association of LRRK2 exonic variants with susceptibility to Parkinson’s disease: a case–control study. Lancet Neurol. 2011;10:898–908. doi: 10.1016/S1474-4422(11)70175-2. PubMed DOI PMC

Mata IF, et al. Lrrk2 R1441G-related Parkinson’s disease: evidence of a common founding event in the seventh century in Northern Spain. Neurogenetics. 2009;10:347–353. doi: 10.1007/s10048-009-0187-z. PubMed DOI PMC

Ishihara L, et al. Clinical features of Parkinson disease patients with homozygous leucine-rich repeat kinase 2 G2019S mutations. Arch. Neurol. 2006;63:1250. doi: 10.1001/archneur.63.9.1250. PubMed DOI

Lesage S, et al. LRRK2 G2019S as a cause of Parkinson’s disease in North African Arabs. N. Engl. J. Med. 2006;354:422–423. doi: 10.1056/NEJMc055540. PubMed DOI

Ozelius LJ, et al. LRRK2 G2019S as a cause of Parkinson’s disease in Ashkenazi Jews. N. Engl. J. Med. 2006;354:424–425. doi: 10.1056/NEJMc055509. PubMed DOI

Farrer MJ, et al. Lrrk2 G2385R is an ancestral risk factor for Parkinson’s disease in Asia. Parkinson. Relat. Disord. 2007;13:89–92. doi: 10.1016/j.parkreldis.2006.12.001. PubMed DOI

Voight BF, Kudaravalli S, Wen X, Pritchard JK. A map of recent positive selection in the human genome. PLoS Biol. 2006;4:e72. doi: 10.1371/journal.pbio.0040072. PubMed DOI PMC

Hakimi M, et al. Parkinson’s disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures. J. Neural Transm. 2011;118:795–808. doi: 10.1007/s00702-011-0653-2. PubMed DOI PMC

Wallings RL, Tansey MG. LRRK2 regulation of immune-pathways and inflammatory disease. Biochem. Soc. Trans. 2019;47:1581–1595. doi: 10.1042/BST20180463. PubMed DOI PMC

Gardet A, et al. LRRK2 is involved in the IFN-γ response and host response to pathogens. J. Immunol. 2010;185:5577–5585. doi: 10.4049/jimmunol.1000548. PubMed DOI PMC

Shutinoski B, et al. Lrrk2 alleles modulate inflammation during microbial infection of mice in a sex-dependent manner. Sci. Transl. Med. 2019;11:eaas9292. doi: 10.1126/scitranslmed.aas9292. PubMed DOI

Nalls MA, 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;18:1091–1102. doi: 10.1016/S1474-4422(19)30320-5. PubMed DOI PMC

Jabbari E, et al. Genetic determinants of survival in progressive supranuclear palsy: a genome-wide association study. Lancet Neurol. 2021;20:107–116. doi: 10.1016/S1474-4422(20)30394-X. PubMed DOI PMC

Li YR, et al. Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases. Nat. Med. 2015;21:1018–1027. doi: 10.1038/nm.3933. PubMed DOI PMC

Witoelar A, et al. Genome-wide pleiotropy between Parkinson Disease And Autoimmune Diseases. JAMA Neurol. 2017;74:780. doi: 10.1001/jamaneurol.2017.0469. PubMed DOI PMC

Farrer MJ. Genetics of Parkinson disease: paradigm shifts and future prospects. Nat. Rev. Genet. 2006;7:306–318. doi: 10.1038/nrg1831. PubMed DOI

Alessi DR, Sammler E. LRRK2 kinase in Parkinson’s disease. Science. 2018;360:36–37. doi: 10.1126/science.aar5683. PubMed DOI

The Austrian VPS-35 Investigators Team. et al. VPS35 Parkinson’s disease phenotype resembles the sporadic disease. J. Neural Transm. 2014;121:755–759. doi: 10.1007/s00702-014-1179-1. PubMed DOI

Vilariño-Güell C, et al. VPS35 mutations in Parkinson disease. Am. J. Hum. Genet. 2011;89:162–167. doi: 10.1016/j.ajhg.2011.06.001. PubMed DOI PMC

Mir R, et al. The Parkinson’s disease VPS35[D620N] mutation enhances LRRK2-mediated Rab protein phosphorylation in mouse and human. Biochem. J. 2018;475:1861–1883. doi: 10.1042/BCJ20180248. PubMed DOI PMC

Burke RE, O’Malley K. Axon degeneration in Parkinson’s disease. Exp. Neurol. 2013;246:72–83. doi: 10.1016/j.expneurol.2012.01.011. PubMed DOI PMC

Orenstein SJ, et al. Interplay of LRRK2 with chaperone-mediated autophagy. Nat. Neurosci. 2013;16:394–406. doi: 10.1038/nn.3350. PubMed DOI PMC

Deniston CK, et al. Structure of LRRK2 in Parkinson’s disease and model for microtubule interaction. Nature. 2020;588:344–349. doi: 10.1038/s41586-020-2673-2. PubMed DOI PMC

Bonet‐Ponce L, Cookson MR. LRRK2 recruitment, activity, and function in organelles. FEBS J. 2022;289:6871–6890. doi: 10.1111/febs.16099. PubMed DOI PMC

Gomez RC, Wawro P, Lis P, Alessi DR, Pfeffer SR. Membrane association but not identity is required for LRRK2 activation and phosphorylation of Rab GTPases. J. Cell Biol. 2019;218:4157–4170. doi: 10.1083/jcb.201902184. PubMed DOI PMC

Tian X, Zhou B. Strategies for site-specific recombination with high efficiency and precise spatiotemporal resolution. J. Biol. Chem. 2021;296:100509. doi: 10.1016/j.jbc.2021.100509. PubMed DOI PMC

Crouch DJM, Bodmer WF. Polygenic inheritance, GWAS, polygenic risk scores, and the search for functional variants. Proc. Natl Acad. Sci. 2020;117:18924–18933. doi: 10.1073/pnas.2005634117. PubMed DOI PMC

Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science. 1983;219:979–980. doi: 10.1126/science.6823561. PubMed DOI

Gapminder. https://www.gapminder.org/.

Howlett WP, et al. Neurological disorders in Northern Tanzania: A 6-year prospective hospital-based case series. Afr. Health Sci. 2022;22:269–284. doi: 10.4314/ahs.v22i1.34. PubMed DOI PMC

Cilia R, et al. The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa. Brain J. Neurol. 2014;137:2731–2742. doi: 10.1093/brain/awu195. PubMed DOI PMC

Amod FH, Bhigjee AI. Clinical series of Parkinson’s disease in KwaZulu-Natal, South Africa: Retrospective chart review. J. Neurol. Sci. 2019;401:62–65. doi: 10.1016/j.jns.2019.03.023. PubMed DOI

van Rensburg ZJ, et al. The South African Parkinson’s disease study collection. Mov. Disord. J. Mov. Disord. Soc. 2022;37:230–232. doi: 10.1002/mds.28828. PubMed DOI

Dotchin C, et al. The prevalence of Parkinson’s disease in rural Tanzania. Mov. Disord. J. Mov. Disord. Soc. 2008;23:1567–1672. doi: 10.1002/mds.21898. PubMed DOI

Dekker MCJ, et al. Parkinson’s disease research on the African continent: obstacles and opportunities. Front. Neurol. 2020;11:512. doi: 10.3389/fneur.2020.00512. PubMed DOI PMC

Rizig M, et al. The International Parkinson Disease Genomics Consortium Africa. Lancet Neurol. 2021;20:335. doi: 10.1016/S1474-4422(21)00100-9. PubMed DOI PMC

Dorsey ER, Sherer T, Okun MS, Bloem BR. The emerging evidence of the parkinson pandemic. J. Park. Dis. 2018;8:S3–S8. PubMed PMC

Leray E, Moreau T, Fromont A, Edan G. Epidemiology of multiple sclerosis. Rev. Neurol. 2016;172:3–13. doi: 10.1016/j.neurol.2015.10.006. PubMed DOI

Bjornevik K, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022;375:296–301. doi: 10.1126/science.abj8222. PubMed DOI

Coleman CB, et al. Epstein-barr virus type 2 infects t cells in healthy Kenyan children. J. Infect. Dis. 2017;216:670–677. doi: 10.1093/infdis/jix363. PubMed DOI PMC

Dorsey ER, Bloem BR. The Parkinson pandemic-a call to action. JAMA Neurol. 2018;75:9–10. doi: 10.1001/jamaneurol.2017.3299. PubMed DOI

De Miranda BR, Goldman SM, Miller GW, Greenamyre JT, Dorsey ER. Preventing Parkinson’s disease: an environmental agenda. J. Park. Dis. 2022;12:45–68. PubMed PMC

Ascherio A, Schwarzschild MA. The epidemiology of Parkinson’s disease: risk factors and prevention. Lancet Neurol. 2016;15:1257–1272. doi: 10.1016/S1474-4422(16)30230-7. PubMed DOI

Narayan S, Liew Z, Bronstein JM, Ritz B. Occupational pesticide use and Parkinson’s disease in the Parkinson Environment Gene (PEG) study. Environ. Int. 2017;107:266–273. doi: 10.1016/j.envint.2017.04.010. PubMed DOI PMC

Schneider Medeiros M, et al. Occupational pesticide exposure and the risk of death in patients with Parkinson’s disease: an observational study in southern Brazil. Environ. Health Glob. Access Sci. Source. 2020;19:68. PubMed PMC

Gamache P-L, et al. Exposure to pesticides and welding hastens the age-at-onset of Parkinson’s disease. Can. J. Neurol. Sci. J. Can. Sci. Neurol. 2019;46:711–716. doi: 10.1017/cjn.2019.248. PubMed DOI

Poortvliet PC, Gluch A, Silburn PA, Mellick GD. The Queensland Parkinson’s Project: an overview of 20 years of mortality from Parkinson’s disease. J. Mov. Disord. 2021;14:34–41. doi: 10.14802/jmd.20034. PubMed DOI PMC

See WZC, Naidu R, Tang KS. Cellular and molecular events leading to paraquat-induced apoptosis: mechanistic insights into parkinson’s disease pathophysiology. Mol. Neurobiol. 2022;59:3353–3369. doi: 10.1007/s12035-022-02799-2. PubMed DOI PMC

Tangamornsuksan W, et al. Paraquat exposure and Parkinson’s disease: a systematic review and meta-analysis. Arch. Environ. Occup. Health. 2019;74:225–238. doi: 10.1080/19338244.2018.1492894. PubMed DOI

Tanner CM, et al. Rotenone, paraquat, and Parkinson’s disease. Environ. Health Perspect. 2011;119:866–872. doi: 10.1289/ehp.1002839. PubMed DOI PMC

Tanner CM, et al. Occupation and risk of parkinsonism: a multicenter case-control study. Arch. Neurol. 2009;66:1106–1113. doi: 10.1001/archneurol.2009.195. PubMed DOI

Costello S, Cockburn M, Bronstein J, Zhang X, Ritz B. Parkinson’s disease and residential exposure to maneb and paraquat from agricultural applications in the central valley of California. Am. J. Epidemiol. 2009;169:919–926. doi: 10.1093/aje/kwp006. PubMed DOI PMC

Tsai W-T. A review on environmental exposure and health risks of herbicide paraquat. Toxicol. Environ. Chem. 2013;95:197–206. doi: 10.1080/02772248.2012.761999. DOI

Langston JW. The MPTP story. J. Park. Dis. 2017;7:S11–S19. PubMed PMC

Vellingiri B, et al. Neurotoxicity of pesticides—a link to neurodegeneration. Ecotoxicol. Environ. Saf. 2022;243:113972. doi: 10.1016/j.ecoenv.2022.113972. PubMed DOI

Cory-Slechta DA, Thiruchelvam M, Barlow BK, Richfield EK. Developmental pesticide models of the Parkinson disease phenotype. Environ. Health Perspect. 2005;113:1263–1270. doi: 10.1289/ehp.7570. PubMed DOI PMC

Spillantini MG, et al. Alpha-synuclein in Lewy bodies. Nature. 1997;388:839–840. doi: 10.1038/42166. PubMed DOI

Polymeropoulos MH, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science. 1997;276:2045–2047. doi: 10.1126/science.276.5321.2045. PubMed DOI

Houser MC, Tansey MG. The gut-brain axis: is intestinal inflammation a silent driver of Parkinson’s disease pathogenesis? NPJ Park. Dis. 2017;3:3. doi: 10.1038/s41531-016-0002-0. PubMed DOI PMC

Funayama M, et al. CHCHD2 mutations in autosomal dominant late-onset Parkinson’s disease: a genome-wide linkage and sequencing study. Lancet Neurol. 2015;14:274–282. doi: 10.1016/S1474-4422(14)70266-2. PubMed DOI

Horsager J, et al. Brain-first versus body-first Parkinson’s disease: a multimodal imaging case-control study. Brain. 2020;143:3077–3088. doi: 10.1093/brain/awaa238. PubMed DOI

Khairnar A, et al. Late-stage α-synuclein accumulation in TNWT-61 mouse model of Parkinson’s disease detected by diffusion kurtosis imaging. J. Neurochem. 2016;136:1259–1269. doi: 10.1111/jnc.13500. PubMed DOI

Khairnar A, et al. Early and progressive microstructural brain changes in mice overexpressing human α-Synuclein detected by diffusion kurtosis imaging. Brain Behav. Immun. 2017;61:197–208. doi: 10.1016/j.bbi.2016.11.027. PubMed DOI

Arab A, et al. Diffusion Kurtosis imaging detects microstructural changes in a methamphetamine-induced mouse model of Parkinson’s disease. Neurotox. Res. 2019;36:724–735. doi: 10.1007/s12640-019-00068-0. PubMed DOI

Khairnar A, et al. Diffusion Kurtosis imaging detects the time-dependent progress of pathological changes in the oral rotenone mouse model of Parkinson’s disease. J. Neurochem. 2021;158:779–797. doi: 10.1111/jnc.15449. PubMed DOI

Sejnoha Minsterova A, et al. Patterns of diffusion kurtosis changes in Parkinson’s disease subtypes. Parkinson. Relat. Disord. 2020;81:96–102. doi: 10.1016/j.parkreldis.2020.10.032. PubMed DOI

Tremblay C, et al. Brain atrophy progression in Parkinson’s disease is shaped by connectivity and local vulnerability. Brain Commun. 2021;3:fcab269. doi: 10.1093/braincomms/fcab269. PubMed DOI PMC

Mitterová K, et al. Dynamic functional connectivity signifies the joint impact of dance intervention and cognitive reserve. Front Aging Neurosci. 2021;13:724094. doi: 10.3389/fnagi.2021.724094. PubMed DOI PMC

Lamoš M, Morávková I, Ondráček D, Bočková M, Rektorová I. Altered spatiotemporal dynamics of the resting brain in mild cognitive impairment with lewy bodies. Mov. Disord. 2021;36:2435–2440. doi: 10.1002/mds.28741. PubMed DOI

Anderkova L, Barton M, Rektorova I. Striato-cortical connections in Parkinson’s and Alzheimer’s diseases: relation to cognition. Mov. Disord. 2017;32:917–922. doi: 10.1002/mds.26956. PubMed DOI

Klobušiaková P, Mareček R, Fousek J, Výtvarová E, Rektorová I. Connectivity between brain networks dynamically reflects cognitive status of parkinson’s disease: a longitudinal study. J. Alzheimers Dis. 2019;67:3233–180834. doi: 10.3233/JAD-180834. PubMed DOI PMC

Bonanni L, et al. Hyperconnectivity in dementia is early and focal and wanes with progression. Cereb. Cortex. 2021;31:97–105. doi: 10.1093/cercor/bhaa209. PubMed DOI

Schumacher J, et al. Dysfunctional brain dynamics and their origin in Lewy body dementia. Brain. 2019;142:1767–1782. doi: 10.1093/brain/awz069. PubMed DOI PMC

Farrow SL, Cooper AA, O’Sullivan JM. Redefining the hypotheses driving Parkinson’s diseases research. Npj Park. Dis. 2022;8:1–7. PubMed PMC

Engelender S, Isacson O. The threshold theory for Parkinson’s disease. Trends Neurosci. 2017;40:4–14. doi: 10.1016/j.tins.2016.10.008. PubMed DOI

Mou L, Ding W, Fernandez-Funez P. Open questions on the nature of Parkinson’s disease: from triggers to spreading pathology. J. Med. Genet. 2020;57:73–81. doi: 10.1136/jmedgenet-2019-106210. PubMed DOI

Rösler TW, et al. K-variant BCHE and pesticide exposure: Gene-environment interactions in a case-control study of Parkinson’s disease in Egypt. Sci. Rep. 2018;8:16525. doi: 10.1038/s41598-018-35003-4. PubMed DOI PMC

Davey GP, Peuchen S, Clark JB. Energy thresholds in brain mitochondria. Potential Involv. Neurodegener. J. Biol. Chem. 1998;273:12753–12757. PubMed

Cannon JR, Greenamyre JT. Gene-environment interactions in Parkinson’s disease: specific evidence in humans and mammalian models. Neurobiol. Dis. 2013;57:38–46. doi: 10.1016/j.nbd.2012.06.025. PubMed DOI PMC

Gao X, et al. Gene-gene interaction between FGF20 and MAOB in Parkinson disease. Ann. Hum. Genet. 2008;72:157–162. doi: 10.1111/j.1469-1809.2007.00418.x. PubMed DOI

Bellou V, Belbasis L, Tzoulaki I, Evangelou E, Ioannidis JPA. Environmental risk factors and Parkinson’s disease: an umbrella review of meta-analyses. Parkinson. Relat. Disord. 2016;23:1–9. doi: 10.1016/j.parkreldis.2015.12.008. PubMed DOI

Olanow CW, Prusiner SB. Is Parkinson’s disease a prion disorder? Proc. Natl Acad. Sci. USA. 2009;106:12571–12572. doi: 10.1073/pnas.0906759106. PubMed DOI PMC

Luk KC, et al. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science. 2012;338:949–953. doi: 10.1126/science.1227157. PubMed DOI PMC

Dächsel JC, Farrer MJ. LRRK2 and Parkinson disease. Arch. Neurol. 2010;67:542–547. doi: 10.1001/archneurol.2010.79. PubMed DOI

Siderowf A, Lang AE. Premotor Parkinson’s disease: concepts and definitions. Mov. Disord. J. Mov. Disord. Soc. 2012;27:608–616. doi: 10.1002/mds.24954. PubMed DOI PMC

Bloem BR, Okun MS, Klein C. Parkinson’s disease. Lancet. 2021;397:2284–2303. doi: 10.1016/S0140-6736(21)00218-X. PubMed DOI

Lange LM, et al. Nomenclature of genetic movement disorders: recommendations of the international parkinson and movement disorder society task force—an update. Mov. Disord. J. Mov. Disord. Soc. 2022;37:905–935. doi: 10.1002/mds.28982. PubMed DOI

Skrahina V, et al. The Rostock International Parkinson’s Disease (ROPAD) study: protocol and initial findings. Mov. Disord. J. Mov. Disord. Soc. 2021;36:1005–1010. doi: 10.1002/mds.28416. PubMed DOI PMC

Choi ML, et al. Pathological structural conversion of α-synuclein at the mitochondria induces neuronal toxicity. Nat. Neurosci. 2022;25:1134–1148. doi: 10.1038/s41593-022-01140-3. PubMed DOI PMC

Pramstaller PP, et al. Lewy body Parkinson’s disease in a large pedigree with 77 Parkin mutation carriers. Ann. Neurol. 2005;58:411–422. doi: 10.1002/ana.20587. PubMed DOI

Tabrizi SJ, et al. A biological classification of Huntington’s disease: the Integrated Staging System. Lancet Neurol. 2022;21:632–644. doi: 10.1016/S1474-4422(22)00120-X. PubMed DOI

Braz BY, et al. Treating early postnatal circuit defect delays Huntington’s disease onset and pathology in mice. Science. 2022;377:eabq5011. doi: 10.1126/science.abq5011. PubMed DOI

Trinh J, Klein C. Needle in a haystack: the common can inform the rare in restless legs syndrome. Ann. Neurol. 2020;87:172–174. doi: 10.1002/ana.25663. PubMed DOI

S B-C, et al. The genetic architecture of Parkinson Disease in Spain: characterizing population-specific risk, differential haplotype structures, and providing etiologic insight. Mov. Disord. J. Mov. Disord. Soc. 2019;34:1851–1863. doi: 10.1002/mds.27864. PubMed DOI PMC

Koch S, et al. Validity and prognostic value of a polygenic risk score for Parkinson’s disease. Genes. 2021;12:1859. doi: 10.3390/genes12121859. PubMed DOI PMC

Trinh J, et al. Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1/PRKN-linked Parkinson’s disease. Brain J. Neurol. 2022;7:awac464. PubMed PMC

Sarkar S, Raymick J, Imam S. Neuroprotective and therapeutic strategies against parkinson’s disease: recent perspectives. Int. J. Mol. Sci. 2016;17:904. doi: 10.3390/ijms17060904. PubMed DOI PMC

Liu H, et al. Polygenic resilience modulates the penetrance of parkinson disease genetic risk factors. Ann. Neurol. 2022;92:270–278. doi: 10.1002/ana.26416. PubMed DOI PMC

T L, et al. Age at onset of LRRK2 p.Gly2019Ser is related to environmental and lifestyle factors. Mov. Disord. J. Mov. Disord. Soc. 2020;35:1854–1858. doi: 10.1002/mds.28238. PubMed DOI

Calne, D. B. Is ‘Parkinson’s disease’ one disease? J. Neurol. Neurosurg. Psychiatry Suppl, 18–21 (1989). PubMed PMC

Lang AE, et al. Trial of cinpanemab in early Parkinson’s disease. N. Engl. J. Med. 2022;387:408–420. doi: 10.1056/NEJMoa2203395. PubMed DOI

Pagano G, et al. Trial of prasinezumab in early-stage Parkinson’s disease. N. Engl. J. Med. 2022;387:421–432. doi: 10.1056/NEJMoa2202867. PubMed DOI

Yuan X, et al. Fine particulate matter triggers α-synuclein fibrillization and parkinson-like neurodegeneration. Mov. Disord. J. Mov. Disord. Soc. 2022;37:1817–1830. doi: 10.1002/mds.29181. PubMed DOI

Tulisiak CT, Mercado G, Peelaerts W, Brundin L, Brundin P. Can infections trigger alpha-synucleinopathies? Prog. Mol. Biol. Transl. Sci. 2019;168:299–322. doi: 10.1016/bs.pmbts.2019.06.002. PubMed DOI PMC

Bolam JP, Pissadaki EK. Living on the edge with too many mouths to feed: why dopamine neurons die. Mov. Disord. J. Mov. Disord. Soc. 2012;27:1478–1483. doi: 10.1002/mds.25135. PubMed DOI PMC

Kurowska Z, et al. Is axonal degeneration a key early event in Parkinson’s disease? J. Park. Dis. 2016;6:703–707. PubMed

Foffani G, Obeso JA. A cortical pathogenic theory of Parkinson’s disease. Neuron. 2018;99:1116–1128. doi: 10.1016/j.neuron.2018.07.028. PubMed DOI

Monogue B, et al. Alpha-synuclein supports type 1 interferon signalling in neurons and brain tissue. Brain J. Neurol. 2022;145:3622–3636. doi: 10.1093/brain/awac192. PubMed DOI PMC

Smeyne RJ, et al. COVID-19 infection enhances susceptibility to oxidative stress-induced Parkinsonism. Mov. Disord. J. Mov. Disord. Soc. 2022;37:1394–1404. doi: 10.1002/mds.29116. PubMed DOI PMC

Matheoud D, et al. Parkinson’s disease-related proteins PINK1 and Parkin repress mitochondrial antigen presentation. Cell. 2016;166:314–327. doi: 10.1016/j.cell.2016.05.039. PubMed DOI

Del Rey NL-G, García-Cabezas MÁ. Cytology, architecture, development, and connections of the primate striatum: Hints for human pathology. Neurobiol. Dis. 2022;176:105945. PubMed

Barer Y, Chodick G, Glaser Chodick N, Gurevich T. Risk of Parkinson disease among adults with vs without posttraumatic stress disorder. JAMA Netw. Open. 2022;5:e2225445. doi: 10.1001/jamanetworkopen.2022.25445. PubMed DOI PMC

Barnat M, et al. Huntington’s disease alters human neurodevelopment. Science. 2020;369:787–793. doi: 10.1126/science.aax3338. PubMed DOI PMC

Brandebura AN, Paumier A, Onur TS, Allen NJ. Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders. Nat. Rev. Neurosci. 2022;24:23–39. doi: 10.1038/s41583-022-00641-1. PubMed DOI PMC

Stoessl AJ. Glucose utilization: still in the synapse. Nat. Neurosci. 2017;20:382–384. doi: 10.1038/nn.4513. PubMed DOI

Chen C, et al. Astrocytic changes in mitochondrial oxidative phosphorylation protein levels in Parkinson’s disease. Mov. Disord. J. Mov. Disord. Soc. 2022;37:302–314. doi: 10.1002/mds.28849. PubMed DOI

Sonninen T-M, et al. Metabolic alterations in Parkinson’s disease astrocytes. Sci. Rep. 2020;10:14474. doi: 10.1038/s41598-020-71329-8. PubMed DOI PMC

de Rus Jacquet A, et al. The LRRK2 G2019S mutation alters astrocyte-to-neuron communication via extracellular vesicles and induces neuron atrophy in a human iPSC-derived model of Parkinson’s disease. eLife. 2021;10:e73062. doi: 10.7554/eLife.73062. PubMed DOI PMC

Iovino L, et al. Trafficking of the glutamate transporter is impaired in LRRK2-related Parkinson’s disease. Acta Neuropathol. 2022;144:81–106. doi: 10.1007/s00401-022-02437-0. PubMed DOI PMC

Streubel-Gallasch L, et al. Parkinson’s disease-associated LRRK2 interferes with astrocyte-mediated alpha-synuclein clearance. Mol. Neurobiol. 2021;58:3119–3140. doi: 10.1007/s12035-021-02327-8. PubMed DOI PMC

Yun SP, et al. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nat. Med. 2018;24:931–938. doi: 10.1038/s41591-018-0051-5. PubMed DOI PMC

Wakabayashi K, Takahashi H, Takeda S, Ohama E, Ikuta F. Parkinson’s disease: the presence of Lewy bodies in Auerbach’s and Meissner’s plexuses. Acta Neuropathol. 1988;76:217–221. doi: 10.1007/BF00687767. PubMed DOI

Adams-Carr KL, et al. Constipation preceding Parkinson’s disease: a systematic review and meta-analysis. J. Neurol. Neurosurg. Psychiatry. 2016;87:710–716. doi: 10.1136/jnnp-2015-311680. PubMed DOI

Knudsen K, et al. In-vivo staging of pathology in REM sleep behaviour disorder: a multimodality imaging case-control study. Lancet Neurol. 2018;17:618–628. doi: 10.1016/S1474-4422(18)30162-5. PubMed DOI

Schrag A, Horsfall L, Walters K, Noyce A, Petersen I. Prediagnostic presentations of Parkinson’s disease in primary care: a case-control study. Lancet Neurol. 2015;14:57–64. doi: 10.1016/S1474-4422(14)70287-X. PubMed DOI

Shannon KM, et al. Alpha-synuclein in colonic submucosa in early untreated Parkinson’s disease: colonic α-Synuclein in Parkinson’s disease. Mov. Disord. 2012;27:709–715. doi: 10.1002/mds.23838. PubMed DOI

Breen DP, Halliday GM, Lang AE. Gut–brain axis and the spread of α‐synuclein pathology: vagal highway or dead end? Mov. Disord. 2019;34:307–316. doi: 10.1002/mds.27556. PubMed DOI

Tan AH, Lim SY, Lang AE. The microbiome–gut–brain axis in Parkinson disease—from basic research to the clinic. Nat. Rev. Neurol. 2022;18:476–495. doi: 10.1038/s41582-022-00681-2. PubMed DOI

Braak H, et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging. 2003;24:197–211. doi: 10.1016/S0197-4580(02)00065-9. PubMed DOI

Borghammer P, et al. A postmortem study suggests a revision of the dual-hit hypothesis of Parkinson’s disease. Npj Park. Dis. 2022;8:166. doi: 10.1038/s41531-022-00436-2. PubMed DOI PMC

Arotcarena M-L, et al. Bidirectional gut-to-brain and brain-to-gut propagation of synucleinopathy in non-human primates. Brain. 2020;143:1462–1475. doi: 10.1093/brain/awaa096. PubMed DOI

Leclair‐Visonneau L, Neunlist M, Derkinderen P, Lebouvier T. The gut in Parkinson’s disease: bottom‐up, top‐down, or neither? Neurogastroenterol. Motil. 2020;32:e13777. doi: 10.1111/nmo.13777. PubMed DOI

Devos D, et al. Colonic inflammation in Parkinson’s disease. Neurobiol. Dis. 2013;50:42–48. doi: 10.1016/j.nbd.2012.09.007. PubMed DOI

Hor JW, et al. Fecal calprotectin in Parkinson’s disease and multiple system atrophy. J. Mov. Disord. 2022;15:106–114. doi: 10.14802/jmd.21085. PubMed DOI PMC

Houser MC, et al. Stool immune profiles evince gastrointestinal inflammation in Parkinson’s disease: stool inflammatory profiles in PD patients. Mov. Disord. 2018;33:793–804. doi: 10.1002/mds.27326. PubMed DOI PMC

Herrick MK, Tansey MG. Is LRRK2 the missing link between inflammatory bowel disease and Parkinson’s disease? Npj Park. Dis. 2021;7:26. doi: 10.1038/s41531-021-00170-1. PubMed DOI PMC

Lin C, et al. Mild chronic colitis triggers Parkinsonism in LRRK2 mutant mice through activating TNF‐α pathway. Mov. Disord. 2022;37:745–757. doi: 10.1002/mds.28890. PubMed DOI

Tan AH, et al. Gut Microbial ecosystem in Parkinson disease: new clinicobiological insights from multi‐omics. Ann. Neurol. 2021;89:546–559. doi: 10.1002/ana.25982. PubMed DOI

Toh TS, et al. Gut microbiome in Parkinson’s disease: new insights from meta-analysis. Parkinson. Relat. Disord. 2022;94:1–9. doi: 10.1016/j.parkreldis.2021.11.017. PubMed DOI

Wallen ZD, et al. Metagenomics of Parkinson’s disease implicates the gut microbiome in multiple disease mechanisms. Nat. Commun. 2022;13:6958. doi: 10.1038/s41467-022-34667-x. PubMed DOI PMC

Sampson TR, et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell. 2016;167:1469–1480.e12. doi: 10.1016/j.cell.2016.11.018. PubMed DOI PMC

Derkinderen P, Shannon KM, Brundin P. Gut feelings about smoking and coffee in Parkinson’s disease: smoking, coffee, and gut microbiota in PD. Mov. Disord. 2014;29:976–979. doi: 10.1002/mds.25882. PubMed DOI PMC

Killinger B, Labrie V. The appendix in Parkinson’s disease: from vestigial remnant to vital organ? J. Park. Dis. 2019;9:S345–S358. PubMed PMC

Matheoud D, et al. Intestinal infection triggers Parkinson’s disease-like symptoms in Pink1−/− mice. Nature. 2019;571:565–569. doi: 10.1038/s41586-019-1405-y. PubMed DOI

Lim S-Y, et al. Parkinson’s disease in the Western Pacific Region. Lancet Neurol. 2019;18:865–879. doi: 10.1016/S1474-4422(19)30195-4. PubMed DOI

Tan, A. H. et al. Probiotics for constipation in Parkinson’s disease: a randomized placebo-controlled study. Neurology 10.1212/WNL.0000000000010998 10.1212/WNL.0000000000010998 (2020). PubMed

ICD-10 Version:2019. https://icd.who.int/browse10/2019/en#/G20-G26.

Dorsey ER, et al. Global, regional, and national burden of Parkinson’s disease, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2018;17:939–953. doi: 10.1016/S1474-4422(18)30295-3. PubMed DOI PMC

Yang W, et al. Current and projected future economic burden of Parkinson’s disease in the U.S. NPJ Park. Dis. 2020;6:15. doi: 10.1038/s41531-020-0117-1. PubMed DOI PMC

Leiva AM, et al. Parkinson’s disease in Chile: highest prevalence in Latin America. Rev. Med. Chil. 2019;147:535–536. doi: 10.4067/S0034-98872019000400535. PubMed DOI

Sepúlveda D, et al. Insulin-like growth factor 2 and autophagy gene expression alteration arise as potential biomarkers in Parkinson’s disease. Sci. Rep. 2022;12:2038. doi: 10.1038/s41598-022-05941-1. PubMed DOI PMC

Early Changes in the Locus Coeruleus in Mild Cognitive Impairment with Lewy Bodies