Parkinson's Disease Mechanisms and Treatments

Dystrophic changes of nigrostriatal axons harboring a Synj1 Parkinson mutation suggest catastrophic failure of endocytic mechanisms

Focal dopaminergic axon swellings in the dorsolateral striatum of Synj1 R259Q mutant mice are clusters of DAT-rich, onion-like plasma membrane invaginations, and the same region shows reduced evoked dopamine release.

Preformed Fibril Seeding Reshapes the Phosphorylated α-Synuclein Proximal Proteome in the Olfactory Bulb

Proximity proteomics in PFF-seeded mouse olfactory bulb shows aggregated phospho-S129 alpha-synuclein mostly reprioritizes existing interactions toward axon-glia, myelin and proteostasis proteins, with a conserved 107-protein signature.

Faecalibacterium prausnitzii, depleted in the Parkinson's disease microbiome, improves motor deficits in α-synuclein overexpressing mice

Oral Faecalibacterium prausnitzii, the taxon most consistently depleted in PD stool, improved motor and GI deficits and lowered α-synuclein aggregates in male Thy1-ASO mice.

LRRK2-mutant microglia and neuromelanin synergize to drive dopaminergic neurodegeneration in an iPSC-based Parkinson's disease model

LRRK2 G2019S iPSC-derived microglia exposed to neuromelanin, but not α-synuclein fibrils, reduce healthy dopaminergic neuron numbers in co-culture; ivermectin prevents this, and post-mortem midbrain supports it.

Type-II kinase inhibitors that target Parkinson's Disease-associated LRRK2

Hybrid type-II inhibitors RN277 and RN341 target inactive LRRK2 with far fewer kinase off-targets than Rebastinib, preserve S935 phosphorylation, and rescue kinesin motility in vitro.

Novel Parkinson's Disease Genetic Risk Factors Within and Across European Populations

A cross-European Parkinson's disease GWAS meta-analysis of 63,555 cases, 17,700 proxy cases and 1,746,386 controls finds 134 risk loci (59 novel), 157 independent signals, and brain-enriched risk genes.

Genome-wide Association Identifies Novel Etiological Insights Associated with Parkinsons Disease in African and African Admixed Populations

Intronic GBA1 variant rs3115534-G, common in African and African admixed ancestry but rare elsewhere, raises Parkinson's disease risk (OR 1.58) and lowers onset age.

Expanding Parkinson’s disease genetics: novel risk loci, genomic context, causal insights and heritable risk

Across 37,688 Parkinson's cases, 18,618 proxy-cases and 1.4M controls, 90 risk signals map to 78 loci (37 new); an 1805-variant polygenic score explains 26-36% of heritability.