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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