Autophagy Process in Parkinson’s Disease Depends on Mutations in the GBA1 and LRRK2 Genes

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Abstract
Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons and abnormal aggregation of the alpha-synuclein protein. Disruption of the autophagy-lysosomal pathway is closely associated with PD pathogenesis. Here, using western-blot analysis we assessed the level of autophagy-related proteins, including phosphorylated mTOR (p-mTOR), phosphorylated RPS6 (p-RPS6), beclin-1 (BECN1), LC3B, p62, and cathepsin D (CTSD) in macrophages derived from peripheral blood mononuclear cells (PBMC-derived macrophages) of GBA1-PD (p.N370S/N, p.L444P/N), LRRK2-PD (p.G2019S/N), idiopathic PD (iPD) patients, and healthy controls. Our findings revealed mutation-specific disruptions in autophagy pathways among PD patients. In p.N370S-GBA1-PD, PBMC-derived macrophages exhibited elevated levels of p-RPS6, BECN1, LC3B-II and decreased mature form of CTSD levels suggesting more active mTOR-dependent autophagy initiation alongside potential autophagosome accumulation that may lead to downregulation of lysosomal degradation. p.L444P-GBA1-PD PBMC-derived macrophages showed increased levels of p-RPS6 and BECN1, coupled with decreased p62 levels and stable mature form of CTSD and LC3B-II, indicative of enhanced autophagy flux driven by mTOR activity without evident lysosomal dysfunction. In p.G2019S-LRRK2-PD patients, PBMC-derived macrophages demonstrated elevated p-RPS6, LC3B-II, and mature CTSD levels, alongside reduced p62 levels. These changes suggest higher basal autophagosome abundance in steady-state autophagy and turnover, potentially driven by lysosomal alterations rather than direct mTOR dysregulation. These mutation-dependent differences highlight distinct autophagy dynamics in GBA1-PD and LRRK2-PD, underscoring the critical role of genetic mutations in modulating PD pathogenesis. Our results emphasize the necessity for subtype-specific therapeutic strategies targeting autophagy and other mTOR-regulated pathways to address the heterogeneity of PD mechanisms.
Funding Information
  • Russian Science Foundation (24-25-00397)

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