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bioRxiv · 10.1101/2024.10.01.616109

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

Siddiqi, F. H.·Raval, N.·Palner, M.·Nielsen, J. E.·Pocock, R.·Rubinsztein, D. C.·Ejlerskov, P.
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Abstract

Parkinsons disease is a neurodegenerative disease, which is associated with accumulation of -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 -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 -synuclein and huntingtin proteins in various cell models. Here we show that knockdown of murine Tbc1d15 in vivo activates autophagy, reduces -synuclein-mediated neurotoxicity, and improves motor performance. Thus, targeting Tbc1d15 expression may be a therapeutic avenue for neurodegenerative diseases.

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Siddiqi, F. H., Raval, N., Palner, M., Nielsen, J. E., Pocock, R., Rubinsztein, D. C., Ejlerskov, P.. 2024-10-03. Tbc1d15 knockdown in vivo alleviates α-synuclein-induced neurotoxicity by promoting autophagy.. https://doi.org/10.1101/2024.10.01.616109

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