Genetic Mechanisms in Parkinson's Disease Pathogenesis

Parkinson’s disease arises from complex interactions between monogenic mutations and polygenic risk factors that converge on common cellular pathways. Familial forms stem from dominant variants in SNCA and LRRK2 or recessive mutations in PRKN, PINK1 and DJ-1, each perturbing protein clearance, kinase signalling or mitochondrial quality control. Sporadic cases are influenced by risk alleles in GBA, PSAP and numerous non-coding regions that modulate gene expression. Dysfunctional α-synuclein homeostasis, whether through SNCA multiplication or lipid dysregulation, drives Lewy body formation, while defective mitophagy leads to energy failure in vulnerable neurons. Genome-wide studies now reveal copy number variations and enhancer mutations that alter dopaminergic pathways. Patient-derived induced pluripotent stem cell models and genome-edited animals confirm that loss-of-function in auxilin (DNAJC6) disrupts clathrin-mediated endocytosis and that impaired parkin phosphorylation undermines mitophagy. Together, these insights highlight the interplay of protein aggregation, lipid metabolism, vesicular trafficking and mitochondrial maintenance in the pathogenesis of Parkinson’s disease, offering routes to targeted therapies.

Research from Nature Portfolio

Recent studies have shown that prosaposin modulates glycosphingolipid metabolism to maintain lipid homeostasis in dopaminergic neurons, with variants linked to Parkinson’s disease risk. Altered prosaposin levels in plasma, cerebrospinal fluid and post-mortem brain tissue correlate with motor impairment. Conditional deletion of prosaposin in dopamine neurons leads to accumulation of unsaturated lipids, sphingolipid depletion and exacerbated α-synuclein toxicity, while prosaposin overexpression protects against neurodegeneration in rodent parkinsonism models.

Genetic Mechanisms in Parkinson's Disease Pathogenesis publication trend

The graph below shows the total number of articles in genetic mechanisms in parkinson's disease pathogenesis across all publications each year (not limited to Nature Index journals).

Technical terms

α-Synuclein: Neuronal protein prone to aggregation, forming Lewy bodies in Parkinson’s disease pathology.

Copy number variation: Structural genomic alteration leading to gains or losses of DNA segments that affect gene dosage.

Induced pluripotent stem cell (iPSC): Somatic cell reprogrammed to a pluripotent state, used to model patient-specific neuronal dysfunction.

Clathrin-mediated endocytosis: Process by which cells internalise membrane proteins and vesicles, essential for synaptic vesicle recycling.

Mitophagy: Selective autophagic degradation of damaged mitochondria, vital for neuronal survival.

References

1. Prosaposin maintains lipid homeostasis in dopamine neurons and counteracts experimental parkinsonism in rodents. Nature Communications (2023).
2. Whole-genome sequencing reveals an association between small genomic deletions and an increased risk of developing Parkinson’s disease. Experimental & Molecular Medicine (2023).
3. Neurodevelopmental and synaptic defects in DNAJC6 parkinsonism, amenable to gene therapy. Brain (2024).
4. Deficiency of parkin causes neurodegeneration and accumulation of pathological α-synuclein in monkey models. Journal of Clinical Investigation (2024).