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Atg4b-dependent Autophagic Flux Alleviates Huntington’s Disease Progression

Moreira Proenca, Catia and Stoehr, Natacha and Bernhard, Mario and Seger, Shanon and Genoud, Christel and Roscic, Ana and Paganetti, Paolo and Murphy, Leon and Kuhn, Rainer and Bouwmeester, Antonius and Galimberti, Ivan (2013) Atg4b-dependent Autophagic Flux Alleviates Huntington’s Disease Progression. PloS ONE, 8 (7). pp. 1-16.

Abstract

The accumulation of aggregated mutant huntingtin (mHtt) inclusion bodies is involved in Huntigton’s disease (HD) progression. Medium sized-spiny neurons (MSNs) in the corpus striatum are highly vulnerable to mHtt aggregate accumulation and degeneration, but the mechanisms and pathways involved have remained elusive. Here we show that cortico-striatal organotypic slice cultures from HD transgenic mice mimic specific features of HD progression. We then show that induction of autophagy using catalytic inhibitors of mTOR prevents MSNs degeneration in HD cortico-striatal slice cultures. Furthermore, disrupting autophagic flux by overexpressing dominant negative Atg4b in neurons and slice cultures, accelerated mHtt aggregation and neuronal death, suggesting that Atg4b-dependent autophagic flux influences HD progression. Under these circumstances induction of autophagy by inhibiting mTOR was inefficient and did not affect mHtt aggregate accumulation, indicating that mTOR inhibition alleviates HD progression by inducing Atg4b-dependent autophagic flux. These results establish modulators of ATG4b-dependent autophagic flux as new potential targets in the treatment of proteinopathies such as HD.

Item Type: Article
Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/8464

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