title: Effects of Pin1 Loss in Hdh(Q111) Knock-in Mice.
abstract: 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/β-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.
authors.affiliation: International School for Advanced Studies (SISSA), Area of Neuroscience Trieste, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Agostoni
authors.affiliation: International School for Advanced Studies (SISSA), Area of Neuroscience Trieste, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Michelazzi
authors.affiliation: International School for Advanced Studies (SISSA), Area of Neuroscience Trieste, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Maurutto
authors.affiliation: International School for Advanced Studies (SISSA), Area of Neuroscience Trieste, Italy.
authors.forename: Alisia
authors.initials: A
authors.lastname: Carnemolla
authors.affiliation: Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie (LNCIB), Area Science ParkTrieste, Italy; Department of Life Sciences, University of TriesteTrieste, Italy.
authors.forename: Yari
authors.initials: Y
authors.lastname: Ciani
authors.affiliation: International School for Advanced Studies (SISSA), Area of Neuroscience Trieste, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Vatta
authors.affiliation: International School for Advanced Studies (SISSA), Area of Neuroscience Trieste, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Roncaglia
authors.affiliation: International School for Advanced Studies (SISSA), Area of NeuroscienceTrieste, Italy; Department of Health Sciences, University of Piemonte OrientaleNovara, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Zucchelli
authors.affiliation: Department of Life Sciences, University of Trieste Trieste, Italy.
authors.forename: Giampiero
authors.initials: G
authors.lastname: Leanza
authors.affiliation: Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie (LNCIB), Area Science ParkTrieste, Italy; Department of Life Sciences, University of TriesteTrieste, Italy.
authors.forename: Fiamma
authors.initials: F
authors.lastname: Mantovani
authors.affiliation: International School for Advanced Studies (SISSA), Area of NeuroscienceTrieste, Italy; Department of Neuroscience and Brain Technologies, Italian Institute of TechnologyGenova, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Gustincich
authors.affiliation: Department of Health Sciences, University of Piemonte Orientale Novara, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Santoro
authors.affiliation: Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie (LNCIB), Area Science ParkTrieste, Italy; Department of Life Sciences, University of TriesteTrieste, Italy.
authors.forename: Silvano
authors.initials: S
authors.lastname: Piazza
authors.affiliation: Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie (LNCIB), Area Science ParkTrieste, Italy; Department of Life Sciences, University of TriesteTrieste, Italy.
authors.forename: Giannino
authors.initials: G
authors.lastname: Del Sal
authors.affiliation: Department of Health Sciences, University of Piemonte Orientale Novara, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Persichetti
keywords: DNA damage response; Huntington’s disease; Pin1; gliosis; neuronal intranuclear inclusions