HDAC4 reduction: a novel therapeutic strategy to target cytoplasmic huntingtin and ameliorate neurodegeneration

Autor: Gillian P. Bates, Janette Robertson, Herman van der Putten, Christian Landles, Tamara Seredenina, Michal Mielcarek, Erich E. Wanker, Chrystelle Touller, Andreas Weiss, Paul A. Marks, Sophie A. Franklin, Vahri Beaumont, Donna L. Smith, Amyaouch Bradaia, Rachel Butler, Georgina F. Osborne, Kristian Wadel, Linda Inuabasi, Larry Park, Eric N. Olson, Ruth Luthi-Carter
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Male
congenital
hereditary
and neonatal diseases and abnormalities
Mice
129 Strain
Huntingtin
Transcription
Genetic
QH301-705.5
Nerve Tissue Proteins
Biology
Synaptic Transmission
General Biochemistry
Genetics and Molecular Biology
Rotarod performance test
Histone Deacetylases
Epigenesis
Genetic
Mice
mental disorders
medicine
Huntingtin Protein
Animals
Biology (General)
Nuclear protein
Cerebral Cortex
Mice
Knockout
Neurons
Brain-derived neurotrophic factor
General Immunology and Microbiology
Brain-Derived Neurotrophic Factor
General Neuroscience
Neurodegeneration
Nuclear Proteins
medicine.disease
Molecular biology
HDAC4
Cell biology
Mice
Inbred C57BL
Phenotype
Huntington Disease
nervous system
Gene Knockdown Techniques
Rotarod Performance Test
Mice
Inbred CBA
Synopsis
Female
Histone deacetylase
General Agricultural and Biological Sciences
Function and Dysfunction of the Nervous System
Research Article
Zdroj: PLoS Biology
PLoS Biology, Vol 11, Iss 11, p e1001717 (2013)
ISSN: 1545-7885
1544-9173
Popis: HDAC4 histone deacetylase is found to associate with huntingtin in a polyQ-length dependent manner. Reduction of HDAC4 levels in mouse models of Huntington's disease (HD) delays cytoplasmic aggregation in the brain and improves the molecular pathology of HD, providing a potential new therapeutic target.
Histone deacetylase (HDAC) 4 is a transcriptional repressor that contains a glutamine-rich domain. We hypothesised that it may be involved in the molecular pathogenesis of Huntington's disease (HD), a protein-folding neurodegenerative disorder caused by an aggregation-prone polyglutamine expansion in the huntingtin protein. We found that HDAC4 associates with huntingtin in a polyglutamine-length-dependent manner and co-localises with cytoplasmic inclusions. We show that HDAC4 reduction delayed cytoplasmic aggregate formation, restored Bdnf transcript levels, and rescued neuronal and cortico-striatal synaptic function in HD mouse models. This was accompanied by an improvement in motor coordination, neurological phenotypes, and increased lifespan. Surprisingly, HDAC4 reduction had no effect on global transcriptional dysfunction and did not modulate nuclear huntingtin aggregation. Our results define a crucial role for the cytoplasmic aggregation process in the molecular pathology of HD. HDAC4 reduction presents a novel strategy for targeting huntingtin aggregation, which may be amenable to small-molecule therapeutics.
Author Summary Huntington's disease (HD) is a late-onset neurodegenerative disorder caused by protein-folding defects in the huntingtin protein. Mutations in huntingtin can result in extra-long tracts of the amino acid glutamine, resulting in aberrant interactions with other proteins and also causing huntingtin proteins to self-associate and -aggregate. The pathology of HD is therefore associated with nuclear and cytoplasmic aggregates. HDAC4 is a histone deacetylase protein traditionally associated with roles in transcription repression. The HDAC4 protein contains a glutamine-rich domain and in this work we find that HDAC4 associates with huntingtin in a polyglutamine-length-dependent manner and that these proteins co-localise in cytoplasmic inclusions. Importantly, reducing HDAC4 levels delays cytoplasmic aggregate formation and rescues neuronal and cortico-striatal synaptic function in mouse models of HD. In addition, we observe improvements in motor coordination and neurological phenotypes, as well as increased lifespan in these mice. Nuclear huntingin aggregates or transcription regulation, however, remained unaffected when HDAC4 levels were reduced to enable these effects. Our results thus provide valuable insight into separating cytoplasmic and nuclear pathologies, and define a crucial role for cytoplasmic aggregations in HD progression. HDAC4 reduction presents a novel strategy for alleviating the toxicity of huntingtin protein aggregation, thereby influencing the molecular pathology of Huntington's disease. As there are currently no disease-modifying therapeutics available for Huntington's disease, we hope that this HDAC4-mediated regulation may be amenable to small-molecule therapeutics.
Databáze: OpenAIRE
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