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PFF induce LRRK2-Mediated Rab5 Phosphorylation Triggering Lysosomal Dysfunction and Neuronal Senescence [ATAC-seq]

ABSTRACT: While there is significant progress in characterizing the pathogenesis of Parkinson's disease (PD), underlying cell biological events are less well-defined. Increasing evidence suggests that endolysosomal dysfunction is a critical driver of PD pathogenesis. In this study, we explored the impact of preformed α-synuclein fibrils (PFF) on endolysosomal function and downstream events, including activation of cellular senescence pathways. We found that PFF treatment of primary cultures of mouse cortical neurons caused widespread endolysosomal dysfunction. PFF treatment also induced changes in transcriptional reprogramming and chromatin accessibility. To define underlying mechanisms we explored the status of LRRK2, finding that PFF treatment activated LRRK2 on early endosomes where it phosphorylated Rab5. PFF also induced phosphorylation of Rab7. LRRK2 activation was necessary for endolysosomal dysfunction and transcriptional changes as these changes were prevented by pharmacological inhibition of LRRK2 with MLi-2. In addition, Rab5 changes mediated by PFF treatment contributed to changes in chromatin remodeling. These cell biological insights point to a critical role in PD pathogenesis for LRRK2 activation and its engagement of the endolysosomal network and to a novel role for the LRRK2-Rab5 axis in mediating its manifestations.

ORGANISM(S): Mus musculus

PROVIDER: GSE294156 | GEO | 2026/05/13

REPOSITORIES: GEO

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Project description:Parkinson’s disease (PD) is characterized by neuroinflammation, progressive loss of dopaminergic neurons, and accumulation of a-synuclein (a-Syn) into insoluble aggregates called Lewy pathology. The Line 61 a-Syn mouse is an established preclinical model of PD; Thy-1 is used to promote human a-Syn expression, and features of sporadic PD develop at 9-18 months of age. To accelerate the PD phenotypes, we injected sonicated human a-Syn preformed fibrils (PFFs) into the striatum, which produced phospho-Syn (p-a-Syn) inclusions in the substantia nigra pars compacta and significantly increased MHC Class II-positive immune cells. Additionally, there was enhanced infiltration and activation of innate and adaptive immune cells in the midbrain. We then used this new model, Line 61-PFF, to investigate the effect of inhibiting the JAK/STAT signaling pathway, which is critical for regulation of innate and adaptive immune responses. After administration of the JAK1/2 inhibitor AZD1480, immunofluorescence staining showed a significant decrease in p-a-Syn inclusions and MHC Class II expression. Flow cytometry showed reduced infiltration of CD4+ T-cells, CD8+ T-cells, CD19+ B-cells, dendritic cells, macrophages, and endogenous microglia into the midbrain. Importantly, single-cell RNA-Sequencing analysis of CD45+ cells from the midbrain identified 9 microglia clusters, 5 monocyte/macrophage (MM) clusters, and 5 T-cell (T) clusters, in which potentially pathogenic MM4 and T3 clusters were associated with neuroinflammatory responses in Line 61-PFF mice. AZD1480 treatment reduced cell numbers and cluster-specific expression of the antigen-presentation genes H2-Eb1, H2-Aa, H2-Ab1, and Cd74 in the MM4 cluster and proinflammatory genes such as Tnf, Il1b, C1qa, and C1qc in the T3 cluster. Together, these results indicate that inhibiting the JAK/STAT pathway suppresses the activation and infiltration of innate and adaptive cells, reducing neuroinflammation in the Line 61-PFF mouse model.

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PFF induce LRRK2-Mediated Rab5 Phosphorylation Triggering Lysosomal Dysfunction and Neuronal Senescence [ATAC-seq]

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