Abstract
Author SummaryHuntington'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.
Highlights
Huntington’s disease (HD) is a progressive, inherited neurological disorder characterized by severe motor, cognitive, behavioural, and physiological dysfunction for which there is no effective disease-modifying treatment [1]
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
Because Hdac4 knock-out (Hdac4KO) mice die in early postnatal life [21], the HD mutation could not be transferred onto an Hdac4 null background
Summary
Huntington’s disease (HD) is a progressive, inherited neurological disorder characterized by severe motor, cognitive, behavioural, and physiological dysfunction for which there is no effective disease-modifying treatment [1]. Mutant huntingtin (HTT) containing an expanded polyQ stretch has a propensity to selfaggregate to produce a wide-range of oligomeric species and insoluble aggregates and exerts a gain of toxic function through aberrant protein–protein interactions [2]. Huntington’s disease (HD) is a late-onset neurodegenerative disorder caused by protein-folding defects in the huntingtin protein. The pathology of HD is associated with nuclear and cytoplasmic aggregates. HDAC4 is a histone deacetylase protein traditionally associated with roles in transcription repression. Nuclear huntingin aggregates or transcription regulation, remained unaffected when HDAC4 levels were reduced to enable these effects. 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 diseasemodifying therapeutics available for Huntington’s disease, we hope that this HDAC4-mediated regulation may be amenable to small-molecule therapeutics
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