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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Autophagy* / drug effects
-
Autophagy-Related Proteins
-
Biocatalysis / drug effects
-
Cerebral Cortex / drug effects
-
Cerebral Cortex / pathology
-
Cysteine Endopeptidases / metabolism*
-
Disease Models, Animal
-
Disease Progression*
-
Huntingtin Protein
-
Huntington Disease / complications
-
Huntington Disease / metabolism*
-
Huntington Disease / pathology*
-
Morpholines / pharmacology
-
Neostriatum / drug effects
-
Neostriatum / pathology
-
Nerve Degeneration / complications
-
Nerve Degeneration / pathology
-
Nerve Tissue Proteins / metabolism
-
Neurons / drug effects
-
Neurons / metabolism
-
Neurons / pathology
-
Nuclear Proteins / metabolism
-
Phenotype
-
TOR Serine-Threonine Kinases / antagonists & inhibitors
-
TOR Serine-Threonine Kinases / metabolism
Substances
-
Autophagy-Related Proteins
-
Htt protein, mouse
-
Huntingtin Protein
-
Morpholines
-
Nerve Tissue Proteins
-
Nuclear Proteins
-
(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol
-
TOR Serine-Threonine Kinases
-
Atg4b protein, mouse
-
Cysteine Endopeptidases
Grants and funding
All the work was funded by Novartis. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.