Ruegsegger, CélineCélineRuegseggerStucki, DavidDavidStuckiSteiner, SilvioSilvioSteinerAngliker, NicoNicoAnglikerRadecke, JulikaJulikaRadecke0000-0002-5815-5537Keller, EvaEvaKellerZuber, BenoîtBenoîtZuber0000-0001-7725-5579Rüegg, Markus AMarkus ARüeggSaxena, SmitaSmitaSaxena0000-0003-4574-45912024-10-232024-10-232016-01-06https://boris-portal.unibe.ch/handle/20.500.12422/137189Spinocerebellar ataxia type 1 (SCA1), due to the expansion of a polyglutamine repeat within the ubiquitously expressed Ataxin-1 protein, leads to the premature degeneration of Purkinje cells (PCs), the cause of which is poorly understood. Here, we identified the unique proteomic signature of Sca1(154Q/2Q) PCs at an early stage of disease, highlighting extensive alterations in proteins associated with synaptic functioning, maintenance, and transmission. Focusing on Homer-3, a PC-enriched scaffold protein regulating neuronal activity, revealed an early decline in its expression. Impaired climbing fiber-mediated synaptic transmission diminished mTORC1 signaling, paralleling Homer-3 reduction in Sca1(154Q/2Q) PCs. Ablating mTORC1 within PCs or pharmacological inhibition of mTORC1 identified Homer-3 as its downstream target. mTORC1 knockout in Sca1(154Q/2Q) PCs exacerbated and accelerated pathology. Reinstating Homer-3 expression in Sca1(154Q/2Q) PCs attenuated cellular dysfunctions and improved motor deficits. Our work reveals that impaired mTORC1-Homer-3 activity underlies PC susceptibility in SCA1 and presents a promising therapeutic target.en500 - Science::570 - Life sciences; biology600 - Technology::610 - Medicine & healtharticle10.7892/boris.747812674809010.1016/j.neuron.2015.11.033