Therapeutic Potential of the Hsp90/Cdc37 Interaction in Neurodegenerative Diseases

Abstract

Alzheimer's, Huntington's, and Parkinson's are devastating neurodegenerative diseases that are prevalent in the aging population. Patient care costs continue to rise each year, because there is currently no cure or disease modifying treatments for these diseases. Numerous efforts have been made to understand the molecular interactions governing the disease development. These efforts have revealed that the phosphorylation of proteins by kinases may play a critical role in the aggregation of disease-associated proteins, which is thought to contribute to neurodegeneration. Interestingly, a molecular chaperone complex consisting of the 90 kDa heat shock protein (Hsp90) and Cell Division Cycle 37 (Cdc37) has been shown to regulate the maturation of many of these kinases as well as regulate some disease-associated proteins directly. Thus, the Hsp90/Cdc37 complex may represent a potential drug target for regulating proteins linked to neurodegenerative diseases, through both direct and indirect interactions. Herein, we discuss the broad understanding of many Hsp90/Cdc37 pathways and how this protein complex may be a useful target to regulate the progression of neurodegenerative disease.

AR12 increases BAG3 expression via ER stress signaling which is essential for Tau and APP degradation via LC3-associated phagocytosis and macroautophagy

“…Chaperones in cells are complexed with other proteins including BAG3 (associated with HSP70) and AHA1 and CDC37 (associated with HSP90). BAG3, AHA1 and CDC37 have all been linked to AD pathology [24][25][26][27][28][29][30]. BAG3 has been shown to enhance Tau degradation by autophagy [22][23][24].…”

“…HSP90 and AHA1 promote Tau pathogenesis [27]. And CDC37 with HSP90 also acts to maintain Tau stability [28][29][30]. AR12 alone as well as the drug combination increased BAG3 expression (Figure 8 and Supplemental Figure 3).…”

The Neurochaperonopathies: Anomalies of the Chaperone System with Pathogenic Effects in Neurodegenerative and Neuromuscular Disorders

“…Furthermore, considering the importance of mitochondrial activity in neuronal cells, one may assume that nitrated Hsp90 may be associated with acquired NCPs in addition to those for ALS. Acquired NCPs could be the result of PTMs in molecular chaperones and of PTMs in co-chaperones, chaperone co-factors or chaperone interactors, as illustrated by the consequences of phosphorylation of Hsp90/Cdc37 complex [133,135].…”

“…Hsp90 collaborates with the Cell Division Cycle 37 (Cdc37) co-chaperone, forming a HSPC/Cdc37 complex, which binds almost 60% of the kinome preventing aggregation of activated regulators [132]. The co-chaperone Cdc37 is also a target of PTMs [133]. Phosphorylation at serine 13 of Cdc37 by CK2 (casein kinase II) affects the Hsp90/Cdc37 complex in performing its kinases homeostasis activity.…”

Evolutionary and cellular analysis of the dark pseudokinase PSKH2

“…Cdc37 was also previously identified as a PSKH2binding partner in untargeted proteome-wide interactome studies (30,34) and is one of the few interactors captured by commercial BioGRID software. Cdc37 is a molecular chaperone component of the HSP90 complex, which is of particular significance given its role in facilitating the correct folding of multiple members of the human kinome, including CDK4, CDK6, SRC, RAF-1, MOK and AKT (35)(36)(37). HSP90α and HSP90β were also enriched in our affinitycapture MS analysis (Supplementary Table 1).…”