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Atg4b-Dependent Autophagic Flux Alleviates Huntington’s Disease Progression
- 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.
- Subjects :
- Huntingtin
Mouse
lcsh:Medicine
Autophagy-Related Proteins
Inclusion bodies
Molecular Cell Biology
Neurobiology of Disease and Regeneration
lcsh:Science
Cerebral Cortex
Neurons
Huntingtin Protein
Multidisciplinary
TOR Serine-Threonine Kinases
Nuclear Proteins
Neurodegenerative Diseases
Animal Models
Cell biology
Cysteine Endopeptidases
Huntington Disease
Phenotype
Neurology
Disease Progression
Medicine
Research Article
Signal Transduction
Genetically modified mouse
Neural Networks
Morpholines
Nerve Tissue Proteins
Context (language use)
Biology
Signaling Pathways
Model Organisms
Huntington's disease
Autophagy
medicine
Animals
PI3K/AKT/mTOR pathway
lcsh:R
medicine.disease
Neostriatum
Disease Models, Animal
Nerve Degeneration
Biocatalysis
lcsh:Q
Molecular Neuroscience
Flux (metabolism)
Neuroscience
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....2c183241c38982c930aff7c92caf40ac