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bioRxiv · 10.64898/2026.01.08.697160

Environmental Toxin Rotenone Drives LRRK2-Mediated Microtubule, Cilia and Proteostasis Disruption in Parkinson's Disease Model

Flinkman, D.·Deshpande, P.·James, P.·Coffey, E.
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Abstract

Exposure to the environmental toxin rotenone increases risk for Parkinsons disease (PD). However, protein phosphorylation changes induced by rotenone in neural-derived cells have not been reported. We examined the effect of rotenone on the proteome and phosphoproteome of cortex-derived cultures from wild-type and Lrrk2-/- mouse brains. We also analyzed the phosphoproteome of the PD cadaver brain using a previously unanalyzed dataset. Rotenone alters phosphorylation at 904 sites, most of which are unchanged in Lrrk2-/- cultures. Common targets include proteins that control microtubule stability, vesicular transport, and protein clearance via the autophagosomal/lysosomal pathway. Analysis of phosphosites with known function indicate that rotenone activates histone deacetylase-1 and represses the pro-survival transcriptional regulators Mef2C and Mef2D, while inhibiting translation by phosphorylating Eif2b5. These effects do not occur in Lrrk2-/- cultures. This study shows that Lrrk2 is required the earliest rotenone-triggered phospho-signalling events.

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Flinkman, D., Deshpande, P., James, P., Coffey, E.. 2026-01-09. Environmental Toxin Rotenone Drives LRRK2-Mediated Microtubule, Cilia and Proteostasis Disruption in Parkinson's Disease Model. https://doi.org/10.64898/2026.01.08.697160

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