Tbc1d15 knockdown in vivo alleviates α-synuclein-induced neurotoxicity by promoting autophagy

Parkinson’s disease is a neurodegenerative disease, which is associated with accumulation of α-synuclein protein aggregates and Lewy Body formation. These neurotoxic inclusions are especially harmful for dopamine-producing neurons in the substantia nigra of the brain. The cellular degradation system autophagy can reduce neurotoxicity caused by accumulated α-synuclein, by targeting it for degradation. Previously, we demonstrated that human TBC1D15 inhibits autophagy in vitro , resulting in accumulation of neurotoxic protein aggregates. Conversely, lowering the TBC1D15 expression promotes autophagy and degradation of α-synuclein and huntingtin proteins in various cell models. Here we show that knockdown of murine Tbc1d15 in vivo activates autophagy, reduces α-synuclein-mediated neurotoxicity, and improves motor performance. Thus, targeting Tbc1d15 expression may be a therapeutic avenue for neurodegenerative diseases.