Effects of Pin1 Loss in Hdh(Q111) Knock-in Mice

Huntington's disease (HD) is a fatal, dominantly inherited, neurodegenerative disorder due to a pathological expansion of the CAG repeat in the coding region of the HTT gene. In the quest for understanding the molecular basis of neurodegeneration, we have previously demonstrated that the prolyl isomerase Pin1 plays a crucial role in mediating p53-dependent apoptosis triggered by mutant huntingtin (mHtt) in vitro. To assess the effects of the lack of Pin1 in vivo, we have bred Pin1 knock-out mice with Hdh(Q111) knock-in mice, a genetically precise model of HD. We show that Pin1 genetic ablation modifies a portion of Hdh(Q111) phenotypes in a time-dependent fashion. As an early event, Pin1 activity reduces the DNA damage response (DDR). In midlife mice, by taking advantage of next-generation sequencing technology, we show that Pin1 activity modulates a portion of the alterations triggered by mHtt, extending the role of Pin1 to two additional Hdh(Q111) phenotypes: the unbalance in the "synthesis/concentration of hormones", as well as the alteration of "Wnt/\u3b2-catenin signaling". In aging animals, Pin1 significantly increases the number of mHtt-positive nuclear inclusions while it reduces gliosis. In summary, this work provides further support for a role of Pin1 in HD pathogenesis. \ua9 2016 Agostoni, Michelazzi, Maurutto, Carnemolla, Ciani, Vatta, Roncaglia, Zucchelli, Leanza, Mantovani, Gustincich, Santoro, Piazza, Del Sal and Persichetti

PIN1 Modulates Huntingtin Levels and Aggregate Accumulation: An In vitro Model

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

Rrs1 is involved in endoplasmic reticulum stress response in Huntington disease

The induction of Rrs1 expression is one of the earliest events detected in a presymptomatic knock-in mouse model of Huntington disease (HD). Rrs1 up-regulation fulfills the HD criteria of dominance, striatal specificity, and polyglutamine dependence. Here we show that mammalian Rrs1 is localized both in the nucleolus as well as in the endoplasmic reticulum (ER) of neurons. This dual localization is shared with its newly identified molecular partner 3D3/lyric. We then show that both genes are induced by ER stress in neurons. Interestingly, we demonstrate that ER stress is an early event in a presymptomatic HD mouse model that persists throughout the life span of the rodent. We further show that ER stress also occurs in postmortem brains of HD patients