Publication Date

1-24-2023

Journal

Annual Review of Pathology: Mechanisms of Disease

DOI

10.1146/annurev-pathmechdis-031521-034145

PMID

36100231

PMCID

PMC10290758

PubMedCentral® Posted Date

1-24-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Humans, Parkinson Disease, Mitochondria, Mutation, parkinsonism, oligogenic, functional genomics, heterogeneity, GBA, LRRK2, alpha-synuclein, synapse, lysosome, mitochondria

Abstract

Parkinson's disease (PD) is clinically, pathologically, and genetically heterogeneous, resisting distillation to a single, cohesive disorder. Instead, each affected individual develops a virtually unique form of Parkinson's syndrome. Clinical manifestations consist of variable motor and nonmotor features, and myriad overlaps are recognized with other neurodegenerative conditions. Although most commonly characterized by alpha-synuclein protein pathology throughout the central and peripheral nervous systems, the distribution varies and other pathologies commonly modify PD or trigger similar manifestations. Nearly all PD is genetically influenced. More than 100 genes or genetic loci have been identified, and most cases likely arise from interactions among many common and rare genetic variants. Despite its complex architecture, insights from experimental genetic dissection coalesce to reveal unifying biological themes, including synaptic, lysosomal, mitochondrial, andimmune-mediated mechanisms of pathogenesis. This emerging understanding of Parkinson's syndrome, coupled with advances in biomarkers and targeted therapies, presages successful precision medicine strategies.

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