Systematic screening identifies elevated neurovascular BCL-XL in Parkinson’s disease
Systematic screening identifies elevated neurovascular BCL-XL in Parkinson’s disease
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Original abstract
Background Vascular cells are emerging as active players in Parkinson’s disease (PD), yet their molecular contribution to α-Synuclein (α-Syn) pathology remains undefined. Here, we show that human brain pericytes respond in a distinct manner to unique α-Syn strains, with systematic validation identifying BCL-XL as a potential regulator of the neurovascular unit in PD. Methods Primary human brain-derived pericytes were exposed to five recombinant α-Syn strains (Fibrils, Fibrils-65, Fibrils-91, Fibrils-110, and Ribbons). Transcriptomic profiling identified differentially expressed genes (DEGs), which were validated at the protein level using multiplex immunocytochemistry and in situ labelling of post-mortem middle temporal gyrus (MTG) tissue microarrays from PD (n = 24) and neurologically normal (n = 24) cases. Results α-Syn strain exposure produced 300 DEGs with limited overlap between strains. BCL-XL and CSNK1D were upregulated in α-Syn-treated pericytes. In post-mortem PD tissue BCL-XL showed marked pericyte-specific elevation in the MTG and increased pericytic and microglial expression in the substantia nigra. Conclusion BCL-XL emerges as a potential regulator of pericyte and microglial resilience in PD, linking acute α-Syn strain–specific responses in pericytes to broader neurovascular alterations. Its upregulation likely represents a generalised compensatory response to chronic α-Syn–associated stress beyond individual strain effects, identifying BCL-XL as a possible therapeutic target within the neurovascular unit.