CHIP as a therapeutic target for neurological diseases

Shuo Zhang,Zheng-Wei Hu,Chang-He Shi,Yu-Ming Xu,Cheng-Yuan Mao

doi:10.1038/s41419-020-02953-5

Abstract

Carboxy-terminus of Hsc70-interacting protein (CHIP) functions both as a molecular co-chaperone and ubiquitin E3 ligase playing a critical role in modulating the degradation of numerous chaperone-bound proteins. To date, it has been implicated in the regulation of numerous biological functions, including misfolded-protein refolding, autophagy, immunity, and necroptosis. Moreover, the ubiquitous expression of CHIP in the central nervous system suggests that it may be implicated in a wide range of functions in neurological diseases. Several recent studies of our laboratory and other groups have highlighted the beneficial role of CHIP in the pathogenesis of several neurological diseases. The objective of this review is to discuss the possible molecular mechanisms that contribute to the pathogenesis of neurological diseases in which CHIP has a pivotal role, such as stroke, intracerebral hemorrhage, Alzheimer’s disease, Parkinson’s disease, and polyglutamine diseases; furthermore, CHIP mutations could also cause neurodegenerative diseases. Based on the available literature, CHIP overexpression could serve as a promising therapeutic target for several neurological diseases.

Highlights

It is established that proteins fundamentally contribute to the maintenance of cellular function and that protein stability is a major mechanism underlying human disease, such as cancer and neurological diseases
Several traditional Chinese medications can upregulate Carboxy-terminus of Hsc70-interacting protein (CHIP) expression in the cerebral cortex and hippocampus of Alzheimer’s disease (AD) disease models, highlighting the role of CHIP in AD80,81. These results indicate that smallmolecule agonists of CHIP such as sulforaphane may constitute promising drugs that could be used for the treatment of neurological diseases
In this review, we highlighted the neuroprotective role of CHIP in neurological diseases such as stroke, AD, and Parkinson’s disease (PD), and diseases caused by CHIP mutations

Summary

Introduction

It is established that proteins fundamentally contribute to the maintenance of cellular function and that protein stability is a major mechanism underlying human disease, such as cancer and neurological diseases. Anderson et al reported that CHIP expression is upregulated in the postmortem brain tissues of patients after stroke[31], implying that CHIP may play an important role in the pathological mechanism after stroke and may be a potential therapeutic target for neuronal injury. The CHIP-related mechanisms in neuronal degradation or neuronal death vary, these studies have suggested that CHIP could be a promising therapeutic target to prevent brain injury after ischemic stroke. CHIP enhanced parkin-mediated ubiquitination of PaelR, and CHIP strengthened the ability of parkin to inhibit neuronal death induced by Pael-R54 Taken together, these data indicate that CHIP positively regulates parkin E3 activity and might be an excellent therapeutic target for the treatment of parkin-related PD. Emerging evidence has suggested that Aβ and tau may be mechanistically linked[75,76], and exploration of the possible mechanistic links between Aβ and tau

Anisomycin

Findings

Conclusions