The Lancet

Volume 403, Issue 10423, 20–26 January 2024, Pages 293-304
The Lancet

Series
The pathogenesis of Parkinson's disease

https://doi.org/10.1016/S0140-6736(23)01478-2Get rights and content

Summary

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.

Introduction

Parkinson's disease is a common neurodegenerative disorder that causes major disability and an increasing global public health burden related to motor, non-motor, and cognitive features.1 Advances in the genetics of Parkinson's disease, beginning with the identification of α-synuclein as the first autosomal dominant gene for Parkinson's disease, have led to a rapid increase in our understanding of its pathogenesis. The major challenges of understanding the disease include identification of new pathways in the development and progression of the disease, and the correlation of these mechanisms with the heterogeneous clinical manifestations and disease course. A series of mechanism-based Parkinson's disease-modifying trials are planned or in progress, directly related to these advances.2 Some trials are now selecting patients with specific genetic variants, and future therapies will possibly be targeted to disease mechanisms in a stratified medicine approach based on biomarkers and genotype. This Series paper summarises recent advances in the understanding of the pathogenesis of Parkinson's disease and highlights probable future developments.

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Section snippets

Clinical aspects of Parkinson's disease

Parkinson's disease is a clinicopathological syndrome in which progressive asymmetric slowness of movement (bradykinesia), rigidity, tremor, and gait disturbance are associated with neuronal loss and the formation of α-synuclein-containing proteinaceous aggregates in neurons of the substantia nigra, known as Lewy bodies and Lewy neurites.3, 4 Parkinsonism might have diverse pathological underlying causes, including tau, polyglutamine, and Alzheimer's disease pathology, as well as nigral cell

Genetics

Parkinson's disease is a genetic disorder in the narrow sense that some patients have well defined causal rare variants leading to familial disease, and in the broad sense that many patients have polygenic risk for disease based on a series of common risk variants.12 The heritability of Parkinson's disease has been estimated from both twin studies and statistical genetic methods to lie between 22% and 40%, so the cause of Parkinson's disease is likely to have a substantial genetic and

Neuropathology

Clinicopathological correlation was used to define the nosology of Parkinson's disease in the past century, and more recent advances in structural and biochemical pathology in humans and model systems have led to advances in our understanding of the pathogenesis. Lewy bodies and Lewy neurites, first described by Frederic Lewy in 1912, contain the protein α-synuclein, which forms filaments that trap organelles such as mitochondria and lysosomes.23, 24, 25, 26 Pathogenic mutations in α-synuclein

Molecular mechanisms contributing to Parkinson's disease

Identification of genes that are altered in genetic forms of Parkinson's disease has provided a greater understanding of the molecular mechanisms that contribute to pathobiology.45 Disruption of interorganellar homoeostasis, impaired mitochondrial and lysosomal function, altered lipid metabolism, endoplasmic reticulum stress, and defective signalling between the endoplasmic reticulum and mitochondria result in a cascade of events associated with the accumulation of α-synuclein,46, 47 deposition

Immune and inflammatory mechanisms

The host cellular response in terms of inflammation and immunity is also likely to be an important mediator of disease progression and pathogenesis (figure 3). Inflammation was first identified as a component of the neuropathology of Parkinson's disease in the 1980s, when microglial activation68 and elevated inflammatory cytokines69 were described in the post-mortem brains of patients with Parkinson's disease.
Inflammation is well described not only in the CNS, but also in the blood, with

Progression

At a clinicopathological level, the onset of Parkinson's disease probably relates to the loss of a threshold proportion of substantia nigra neurons and the motor effects of loss of dopaminergic innervation of the basal ganglia. Although disease prevention trials have been proposed for people with an increased risk of development of Parkinson's disease (most notably patients with REM sleep behaviour disorder), almost all disease-modifying trials to date have been based on randomisation of a

Pathogenesis-driven biomarkers

Several biomarkers have been used to indicate the extent of neuronal loss and dysfunction, acting as surrogate markers for Parkinson's disease severity and progression. These biomarkers include functional imaging measures of presynaptic nigrostriatal nerve terminals; MRI measures of disruption of nigrosomes, atrophy, and iron deposition;95 and blood neurofilament light, which is a non-specific marker of neuronal damage.94 Progress in our understanding of the pathogenesis of Parkinson's disease

Pathogenesis-driven drug trials

To date, no disease-modifying, neuroprotective treatments for Parkinson's disease have been shown to be effective in phase 3 clinical trials; however, as understanding of the pathogenesis of Parkinson's disease rapidly expands, multiple promising drug targets that might have potential as disease-modifying agents and warrant further consideration in early-phase trials have been identified (table).2 The concept of total SNCA gene expression as a primary driver of disease has led to the

Conclusions

Advances in the understanding of the pathogenesis of Parkinson's disease, driven by neurogenetics, have provided insights into the initiation and progression of the disease. Parkinson's disease relates to the formation of abnormal α-synuclein aggregates both in the periphery and the brain, as well as the spread of this pathology through the brain. This pathology is accompanied by immune activation, neuroinflammation, mitochondrial dysfunction, and changes in lysosomal and endosomal function.

Search strategy and selection criteria

We searched PubMed for review articles published in English between July 11, 2017, and June 26, 2023 that included “Parkinson's” with “pathogenesis” OR ”genetics” OR ”aetiology” OR “biochemistry” OR “pathology”. We also searched the reference lists of articles identified by this search strategy and selected those we judged relevant, supplemented by original articles provided by the authors. Review articles are cited to provide readers with an overview of some aspects of the pathogenesis of

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

References (118)

  • F Singh et al.

    Parkinson's disease and mitophagy: an emerging role for LRRK2

    Biochem Soc Trans

    (2021)
  • J Burtscher et al.

    Fatal attraction - the role of hypoxia when alpha-synuclein gets intimate with mitochondria

    Neurobiol Aging

    (2021)
  • M Horowitz et al.

    Lysosomal functions and dysfunctions: molecular and cellular mechanisms underlying Gaucher disease and its association with Parkinson disease

    Adv Drug Deliv Rev

    (2022)
  • RX Bo et al.

    The neuroinflammatory role of glucocerebrosidase in Parkinson's disease

    Neuropharmacology

    (2022)
  • N Giladi et al.

    Safety and efficacy of venglustat in GBA1-associated Parkinson's disease: an international, multicentre, double-blind, randomised, placebo-controlled, phase 2 trial

    Lancet Neurol

    (2023)
  • M Mogi et al.

    Interleukin-1 β, interleukin-6, epidermal growth factor and transforming growth factor-α are elevated in the brain from parkinsonian patients

    Neurosci Lett

    (1994)
  • F Weiss et al.

    Immune responses in the Parkinson's disease brain

    Neurobiol Dis

    (2022)
  • A Kouli et al.

    Toll-like receptors and their therapeutic potential in Parkinson's disease and α-synucleinopathies

    Brain Behav Immun

    (2019)
  • D Matheoud et al.

    Parkinson's disease-related proteins PINK1 and parkin repress mitochondrial antigen presentation

    Cell

    (2016)
  • MM Alam et al.

    Alpha synuclein, the culprit in Parkinson disease, is required for normal immune function

    Cell Rep

    (2022)
  • A Siderowf et al.

    Assessment of heterogeneity among participants in the Parkinson's Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study

    Lancet Neurol

    (2023)
  • Y Ben-Shlomo et al.

    The epidemiology of Parkinson's disease

    Lancet

    (2024)
  • FH Lewy

    Paralysis agitans. I. Pathologische anatomie

  • WR Gibb et al.

    The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease

    J Neurol Neurosurg Psychiatry

    (1988)
  • JF Geddes et al.

    Pathological overlap in cases of parkinsonism associated with neurofibrillary tangles. A study of recent cases of postencephalitic parkinsonism and comparison with progressive supranuclear palsy and Guamanian parkinsonism-dementia complex

    Brain

    (1993)
  • LV Kalia et al.

    Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease

    JAMA Neurol

    (2015)
  • KM Doherty et al.

    Parkin disease: a clinicopathologic entity?

    JAMA Neurol

    (2013)
  • J-L Wang et al.

    Analysis of SCA2 and SCA3/MJD repeats in Parkinson's disease in mainland China: genetic, clinical, and positron emission tomography findings

    Mov Disord

    (2009)
  • D Caparros-Lefebvre et al.

    Guadeloupean parkinsonism: a cluster of progressive supranuclear palsy-like tauopathy

    Brain

    (2002)
  • JC Steele et al.

    The ALS/PDC syndrome of Guam and the cycad hypothesis

    Neurology

    (2008)
  • RB Postuma et al.

    MDS clinical diagnostic criteria for Parkinson's disease

    Mov Disord

    (2015)
  • CL Xie et al.

    The association between the LRRK2 G2385R variant and the risk of Parkinson's disease: a meta-analysis based on 23 case-control studies

    Neurol Sci

    (2014)
  • M Goedert et al.

    The synucleinopathies: twenty years on.

    J Parkinsons Dis

    (2017)
  • M Goedert et al.

    100 years of Lewy pathology

    Nat Rev Neurol

    (2013)
  • A Singleton et al.

    A generalizable hypothesis for the genetic architecture of disease: pleomorphic risk loci

    Hum Mol Genet

    (2011)
  • M Rizig et al.

    Genome-wide association identifies novel etiological insights associated with Parkinson's disease in African and African admixed populations.

    medRxiv

    (2023)
  • MPM Soutar et al.

    Regulation of mitophagy by the NSL complex underlies genetic risk for Parkinson's disease at 16q11.2 and MAPT H1 loci

    Brain

    (2022)
  • P Holmans et al.

    A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson's disease

    Hum Mol Genet

    (2013)
  • PE Duffy et al.

    Phase and electron microscopic observations of Lewy bodies and melanin granules in the substantia nigra and locus caeruleus in Parkinson's disease

    J Neuropathol Exp Neurol

    (1965)
  • Y Guo et al.

    Genetic analysis and literature review of SNCA variants in Parkinson's disease

    Front Aging Neurosci

    (2021)
  • Y Yang et al.

    Cryo-EM structures of α-synuclein filaments from Parkinson's disease and dementia with Lewy bodies.

    bioRxiv

    (2022)
  • MG Spillantini et al.

    α-Synuclein in Lewy bodies

    Nature

    (1997)
  • A Tozzi et al.

    Dopamine-dependent early synaptic and motor dysfunctions induced by α-synuclein in the nigrostriatal circuit

    Brain

    (2021)
  • L Calo et al.

    Synaptic failure and α-synuclein

    Mov Disord

    (2016)
  • M Schweighauser et al.

    Structures of α-synuclein filaments from multiple system atrophy

    Nature

    (2020)
  • E Lobanova et al.

    Imaging protein aggregates in the serum and cerebrospinal fluid in Parkinson's disease

    Brain

    (2022)
  • P Alam et al.

    α-Synuclein oligomers and fibrils: a spectrum of species, a spectrum of toxicities

    J Neurochem

    (2019)
  • J Horsager et al.

    Brain-first versus body-first Parkinson's disease: a multimodal imaging case-control study

    Brain

    (2020)
  • TG Beach et al.

    Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction

    Acta Neuropathol

    (2009)
  • JH Kordower et al.

    Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease

    Nat Med

    (2008)

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