title: Atg4b-dependent autophagic flux alleviates Huntington's disease progression.
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.
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Catia C
authors.initials: CC
authors.lastname: Proenca
authors.forename: Natacha
authors.initials: N
authors.lastname: Stoehr
authors.forename: Mario
authors.initials: M
authors.lastname: Bernhard
authors.forename: Shanon
authors.initials: S
authors.lastname: Seger
authors.forename: Christel
authors.initials: C
authors.lastname: Genoud
authors.forename: Ana
authors.initials: A
authors.lastname: Roscic
authors.forename: Paolo
authors.initials: P
authors.lastname: Paganetti
authors.forename: Shanming
authors.initials: S
authors.lastname: Liu
authors.forename: Leon O
authors.initials: LO
authors.lastname: Murphy
authors.forename: Rainer
authors.initials: R
authors.lastname: Kuhn
authors.forename: Tewis
authors.initials: T
authors.lastname: Bouwmeester
authors.forename: Ivan
authors.initials: I
authors.lastname: Galimberti
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D000071183:Autophagy-Related Proteins; D055162:Biocatalysis / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D009025:Morpholines / Q000494:pharmacology; D017072:Neostriatum / Q000187:drug effects / Q000473:pathology; D009410:Nerve Degeneration / Q000150:complications / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D010641:Phenotype; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000071183:Autophagy-Related Proteins; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009025:Morpholines; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; D058570:TOR Serine-Threonine Kinases; C582881:Atg4b protein, mouse; D003546:Cysteine Endopeptidases