The pathogenesis of Parkinson's disease

Huw R Morris¹, Maria Grazia Spillantini², Carolyn M Sue³, Caroline H Williams-Gray⁴

Affiliations

¹ Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK; University College London Movement Disorders Centre, University College London, London, UK; Aligning Science Across Parkinson's Collaborative Research Network, Chevy Chase, MD, USA. Electronic address: h.morris@ucl.ac.uk.
² Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; Aligning Science Across Parkinson's Collaborative Research Network, Chevy Chase, MD, USA.
³ Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia; Department of Neurology, South Eastern Sydney Local Health District, Sydney, NSW, Australia; Aligning Science Across Parkinson's Collaborative Research Network, Chevy Chase, MD, USA; Neuroscience Research Australia, Randwick, NSW, Australia. Electronic address: c.sue@neura.edu.au.
⁴ John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

PMID: 38245249
DOI: 10.1016/S0140-6736(23)01478-2

Review

The pathogenesis of Parkinson's disease

Huw R Morris et al. Lancet. 2024.

. 2024 Jan 20;403(10423):293-304.

doi: 10.1016/S0140-6736(23)01478-2.

Authors

Huw R Morris¹, Maria Grazia Spillantini², Carolyn M Sue³, Caroline H Williams-Gray⁴

Affiliations

¹ Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK; University College London Movement Disorders Centre, University College London, London, UK; Aligning Science Across Parkinson's Collaborative Research Network, Chevy Chase, MD, USA. Electronic address: h.morris@ucl.ac.uk.
² Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; Aligning Science Across Parkinson's Collaborative Research Network, Chevy Chase, MD, USA.
³ Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia; Department of Neurology, South Eastern Sydney Local Health District, Sydney, NSW, Australia; Aligning Science Across Parkinson's Collaborative Research Network, Chevy Chase, MD, USA; Neuroscience Research Australia, Randwick, NSW, Australia. Electronic address: c.sue@neura.edu.au.
⁴ John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

PMID: 38245249
DOI: 10.1016/S0140-6736(23)01478-2

Abstract

Parkinson's disease is a progressive neurodegenerative condition associated with the deposition of aggregated α-synuclein. Insights into the pathogenesis of Parkinson's disease have been derived from genetics and molecular pathology. Biochemical studies, investigation of transplanted neurons in patients with Parkinson's disease, and cell and animal model studies suggest that abnormal aggregation of α-synuclein and spreading of pathology between the gut, brainstem, and higher brain regions probably underlie the development and progression of Parkinson's disease. At a cellular level, abnormal mitochondrial, lysosomal, and endosomal function can be identified in both monogenic and sporadic Parkinson's disease, suggesting multiple potential treatment approaches. Recent work has also highlighted maladaptive immune and inflammatory responses, possibly triggered in the gut, that accelerate the pathogenesis of Parkinson's disease. Although there are currently no disease-modifying treatments for Parkinson's disease, we now have a solid basis for the development of rational neuroprotective therapies that we hope will halt the progression of this disabling neurological condition.

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Conflict of interest statement

Declaration of interests HRM is employed by University College London, and in the past 36 months reports paid consultancy from Roche, Aprinoia, and Amylyx; lecture fees and honoraria from the British Medical Journal, Kyowa Kirin, and the Movement Disorder Society; research grants from CBD Solutions, Drake Foundation, Parkinson's UK, Cure Parkinson's Trust, PSP Association, Medical Research Council, and the Michael J Fox Foundation (MJFF); and is a coapplicant on a patent application related to C9ORF72—method for diagnosing a neurodegenerative disease (PCT/GB2012/052140). MGS is a William Scholl Professor supported by the Scholl Foundation endowment to Cambridge University, is supported by the Wellcome Trust, is supported by the NIHR Cambridge Biomedical Research Centre Dementia (NIHR203312) and Neurodegeneration Theme (146281), and in the past 12 months has been paid lecture fees or honoraria, or both, from the Movement Disorder Society and Institute San Raffaele; is on the Scientific Advisory Board of the Tau Consortium, Qatar Biomedical Research Institute, Fondazione Don Gnocchi, Eurac, and the European Brain Research Institute; is a consultant for Astex; is in scientific collaboration with Eli Lilly and Teva; and reports research grants from Parkinson's UK, MJFF, Biotechnology and Biological Sciences Research Council, the Scholl Foundation, Fondation de la Recherche Alzheimer, Alzheimer's Research UK, Medical Research Council, Wellcome Trust, and the Bill & Melinda Gates foundation. CMS is employed by South Eastern Sydney Local Health District, Neuroscience Research Australia, and University of New South Wales; is a National Health and Medical Research Council (NHMRC) Practitioner Fellow (APP1136800); and in the past 12 months, has received research funding from the NHMRC, the Medical Research Futures Fund, MJFF, and Shake It Up Australia; and has been paid lecture fees and honoraria from the Movement Disorder Society and the Taiwan Movement Disorder Society. CHW-G is employed by the University of Cambridge, and in the past 12 months has received research funding from the Medical Research Council (MR/W029235/1), the National Institutes of Health Research (NIHR) Cambridge Biomedical Research Centre (NIHR203312), Parkinson's UK, Cure Parkinson's, the Evelyn Trust, and the Cambridge Centre for Parkinson-Plus; consultancy fees from Evidera; and speaker fees from GSK and the World Parkinson Congress.

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The pathogenesis of Parkinson's disease

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The pathogenesis of Parkinson's disease

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