Cytosol-endoplasmic reticulum interplay by Sec61alpha translocon in polyglutamine-mediated neurotoxicity in Drosophila.

Intracellular deposition of aggregated and ubiquitinated proteins is a prominent cytopathological feature of most neurodegenerative disorders frequently correlated with neural cell death. To elucidate mechanisms in neural cell death and degeneration, we characterized the Drosophila ortholog of Sec61alpha (DSec61alpha), a component of the translocon that is involved in both protein import and endoplasmic reticulum-associated degradation. Loss-of-function experiments for DSec61alpha revealed that the translocon contributes to expanded polyglutamine-mediated neuronal toxicity, likely resulting from proteasome inhibition and leading to accumulation of ubiquitinated proteins. Taken together, proteasome inhibition by expanded polyglutamine tracts may lead to the accumulation of toxic undegraded proteins normally transported by the Sec61alpha translocon.