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Atg4b-Dependent Autophagic Flux Alleviates Huntington’s Disease Progression

Authors :
Shanon Seger
Natacha Stoehr
Mario Bernhard
Christel Genoud
Ivan Galimberti
Catia C. Proenca
Tewis Bouwmeester
Shanming Liu
Rainer Kuhn
Leon Murphy
Ana Roscic
Paolo Paganetti
Source :
PLoS ONE, PLoS ONE, Vol 8, Iss 7, p e68357 (2013)
Publication Year :
2013
Publisher :
Public Library of Science (PLoS), 2013.

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 remain elusive. Here we have developed a new model to study MSNs degeneration in the context of HD. We produced organotypic cortico-striatal slice cultures (CStS) from HD transgenic mice mimicking specific features of HD progression. We then show that induction of autophagy using catalytic inhibitors of mTOR prevents MSNs degeneration in HD CStS. Furthermore, disrupting autophagic flux by overexpressing 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 using catalytic inhibitors of mTOR was inefficient and did not affect mHtt aggregate accumulation and toxicity, 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 HD.

Details

ISSN :
19326203
Volume :
8
Database :
OpenAIRE
Journal :
PLoS ONE
Accession number :
edsair.doi.dedup.....2c183241c38982c930aff7c92caf40ac