Preventing mutant huntingtin proteolysis and intermittent fasting promote autophagy in models of Huntington disease
Posted on 2018-03-06 - 05:00
Abstract Huntington disease (HD) is caused by the expression of mutant huntingtin (mHTT) bearing a polyglutamine expansion. In HD, mHTT accumulation is accompanied by a dysfunction in basal autophagy, which manifests as specific defects in cargo loading during selective autophagy. Here we show that the expression of mHTT resistant to proteolysis at the caspase cleavage site D586 (C6R mHTT) increases autophagy, which may be due to its increased binding to the autophagy adapter p62. This is accompanied by faster degradation of C6R mHTT in vitro and a lack of mHTT accumulation the C6R mouse model with age. These findings may explain the previously observed neuroprotective properties of C6R mHTT. As the C6R mutation cannot be easily translated into a therapeutic approach, we show that a scheduled feeding paradigm is sufficient to lower mHTT levels in YAC128 mice expressing cleavable mHTT. This is consistent with a previous model, where the presence of cleavable mHTT impairs basal autophagy, while fasting-induced autophagy remains functional. In HD, mHTT clearance and autophagy may become increasingly impaired as a function of age and disease stage, because of gradually increased activity of mHTT-processing enzymes. Our findings imply that mHTT clearance could be enhanced by a regulated dietary schedule that promotes autophagy.
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Ehrnhoefer, Dagmar; Martin, Dale; Schmidt, Mandi; Qiu, Xiaofan; Ladha, Safia; Caron, Nicholas; et al. (2018). Preventing mutant huntingtin proteolysis and intermittent fasting promote autophagy in models of Huntington disease. figshare. Collection. https://doi.org/10.6084/m9.figshare.c.4024330.v1