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bioRxiv · 10.64898/2026.05.03.722488

Systematic screening identifies elevated neurovascular BCL-XL in Parkinson's disease.

Reddy, K.·Yin, E.·Wu, X. H.·Stevenson, T. J.·Ryan, B.·Murray, H. C.·Young, D.·Faull, R. L. M.·Curtis, M. A.·Halliday, G.·Melki, R.·Dragunow, M.·Dieriks, B. V.
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Abstract

BackgroundVascular cells are emerging as active players in Parkinsons disease (PD), yet their molecular contribution to -Synuclein (-Syn) pathology remains undefined. Here, we show that human brain pericytes respond in a distinct manner to unique -Syn strains, with systematic validation identifying BCL-XL as a potential regulator of the neurovascular unit in PD. MethodsPrimary human brain-derived pericytes were exposed to five recombinant -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-Syn strain exposure produced 300 DEGs with limited overlap between strains. BCL-XL and CSNK1D were upregulated in -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. ConclusionBCL-XL emerges as a potential regulator of pericyte and microglial resilience in PD, linking acute -Syn strain-specific responses in pericytes to broader neurovascular alterations. Its upregulation likely represents a generalised compensatory response to chronic -Syn-associated stress beyond individual strain effects, identifying BCL-XL as a possible therapeutic target within the neurovascular unit.

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Reddy, K., Yin, E., Wu, X. H., Stevenson, T. J., Ryan, B., Murray, H. C., Young, D., Faull, R. L. M., Curtis, M. A., Halliday, G., Melki, R., Dragunow, M., Dieriks, B. V.. 2026-05-06. Systematic screening identifies elevated neurovascular BCL-XL in Parkinson's disease.. https://doi.org/10.64898/2026.05.03.722488

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