CHIP as a therapeutic target for neurological diseases

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.

LncRNA MIAT enhances cerebral ischaemia/reperfusion injury in rat model via interacting with EGLN2 and reduces its ubiquitin‐mediated degradation

“…(F) Immunoprecipitation assay was used to detect the interaction between EGLN2 N88 and MDM2 in MIAT-knockdown primary rat neurons with 12 h reoxygenation after OGD treatment of some chaperone-bound proteins. 26 NDFIP1 binds to PTEN and enhances its ubiquitination mediated by NEDD4 and nuclear import, thereby promoting neuronal survival following cerebral ischaemia. 27 Therefore, it is necessary to consider the specific functions of ubiquitin ligases in stress regulation and neuronal degeneration.…”

Exploration of Aberrant E3 Ligases Implicated in Alzheimer’s Disease and Development of Chemical Tools to Modulate Their Function

“…Additionally, JNPL3 mice with P301L tau overexpression exhibit decreased CHIP levels in their spinal cords, increased tau inclusions, and neuronal loss, whereas their cerebellar regions demonstrated increased CHIP expression ( Sahara et al, 2005 ). Zhang et al (2020) showed that CHIP can directly bind, attach K48- and K63-linked ubiquitin, and eliminate phosphorylated tau, inducing both proteasomal and autophagic degradation ( Joshi et al, 2016 ). CHIP also interacts with caspase-cleaved tau and is involved in its degradation in cortical neurons ( Dolan and Johnson, 2010 ).…”

Cytosolic protein quality control machinery: Interactions of Hsp70 with a network of co-chaperones and substrates

“…There are numerous implications for the dysregulation of Hsp70 leading to diseases 165,166 These include cancer, 162 central nervous system (CNS) disorders, 167 and cardiovascular diseases. 168 Moreover, the co-chaperones BAG, 105,169,170 Hsp40, 171,172 Hip, 138 HOP, 173 HspBP1, 174 HSP110, 175,176 CHIP, [177][178][179] and SAMDs 162,164 are also implicated in wide variety of diseases. The implications of Hsp70 and co-chaperones in wide range of diseases have led to calls to target these proteins for drug discovery.…”