Abstract
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder characterized by a polyglutamine expansion within the N-terminal region of huntingtin protein (HTT). Cellular mechanisms promoting mutant huntingtin (mHTT) clearance are of great interest in HD pathology as they can lower the level of the mutant protein and its toxic aggregated species, thus affecting disease onset and progression. We have previously shown that the prolyl-isomerase PIN1 represents a promising negative regulator of mHTT aggregate accumulation using a genetically precise HD mouse model, namely HdhQ111 mice. Therefore, the current study aims at underpinning the mechanism by which PIN1 affects huntingtin's aggregates. We found that PIN1 overexpression led to a reduction of mHTT aggregates in HEK293 cells, and that this could be linked to a negative regulation of mHTT half-life by PIN1. Furthermore, we show that PIN1 has the ability to stimulate the proteasome presenting evidence of a mechanism regulating this phenomenon. Our findings provide a rationale for future investigation into PIN1 with the potential for the development of novel therapeutic strategies.
Highlights
Huntington’s disease (HD) is a progressive, dominantly inherited neurodegenerative disorder that usually manifests in mid-life with psychiatric symptoms, followed by motor impairment and cognitive decline (Papoutsi et al, 2014; Pla et al, 2014; Ross et al, 2014; Zielonka et al, 2015)
Since mutant huntingtin (mHTT) accumulations are mainly found in the nuclei of the affected cells in HD post-mortem brains (Difiglia et al, 1997), the possibility to enhance the degradative capacities of the ubiquitin-proteasome system (UPS), which unlike autophagy operates both in the cytoplasm and the nucleus (Schipper-Krom et al, 2012), may counteract the accumulation of mHTT aggregates
We have previously shown that the genetic ablation of pin1 in HdhQ111 knock-in mice (Wheeler et al, 1999; HdhQ111::Pin1−/−) led to an increase of aggregate load in the striatum of these mice (Agostoni et al, 2016)
Summary
Huntington’s disease (HD) is a progressive, dominantly inherited neurodegenerative disorder that usually manifests in mid-life with psychiatric symptoms, followed by motor impairment and cognitive decline (Papoutsi et al, 2014; Pla et al, 2014; Ross et al, 2014; Zielonka et al, 2015). Evidence suggests that mHTT aggregation could start off as a coping cellular response, but aggregates become co-cause of neuronal dysfunction and cell death (Davies et al, 1997; Difiglia et al, 1997; Gutekunst et al, 1999; Borrell-Pagès et al, 2006; Arrasate and Finkbeiner, 2012). The contribution of aggregates to the pathogenesis of HD is not fully understood, the toxicity of soluble monomeric and oligomeric mHTT protein has become a well-accepted evidence (Arrasate and Finkbeiner, 2012) and cellular mechanisms promoting mHTT clearance are of great interest as they could prevent or delay the onset and progression of HD pathology (Sarkar and Rubinsztein, 2008). Since mHTT accumulations are mainly found in the nuclei of the affected cells in HD post-mortem brains (Difiglia et al, 1997), the possibility to enhance the degradative capacities of the UPS, which unlike autophagy operates both in the cytoplasm and the nucleus (Schipper-Krom et al, 2012), may counteract the accumulation of mHTT aggregates
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