PIN1 Modulates Huntingtin Levels and Aggregate Accumulation: An Model

Overview

Journal Front Cell Neurosci

Specialty Cell Biology

Date 2017 May 24

PMID 28533744

Citations 9

Authors

Alisia Carnemolla

Silvia Michelazzi

Elena Agostoni

Affiliations

Soon will be listed here.

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 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.

Citing Articles

Therapeutic approaches targeting aging and cellular senescence in Huntington's disease.

Bhat A, Moglad E, Afzal M, Thapa R, Almalki W, Kazmi I CNS Neurosci Ther. 2024; 30(10):e70053.

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Pin1-catalyzed conformational regulation after phosphorylation: A distinct checkpoint in cell signaling and drug discovery.

Lu K, Zhou X Sci Signal. 2024; 17(841):eadi8743.

PMID: 38889227 PMC: 11409840. DOI: 10.1126/scisignal.adi8743.

Pin1-Catalyzed Conformation Changes Regulate Protein Ubiquitination and Degradation.

Jeong J, Usman M, Li Y, Zhou X, Lu K Cells. 2024; 13(9.

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The regulatory role of Pin1 in neuronal death.

Wang S, Hu X, Xiong K Neural Regen Res. 2022; 18(1):74-80.

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New PIN1 inhibitors identified through a pharmacophore-driven, hierarchical consensus docking strategy.

Poli G, Di Stefano M, Estevez J, Minutolo F, Granchi C, Giordano A J Enzyme Inhib Med Chem. 2021; 37(1):145-150.

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