Cdc37: Implications in Regulation of Kinases and Proteins Linked to Neurodegenerative and Other Diseases

Abstract Autophagy is a cellular process that is important for removal and recycling of misfolded proteins and damaged cellular components, and maintenance of cellular homeostasis especially in neurons. Autophagic dysfunction has been reported in a number of other neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease, lateral sclerosis (ALS), and Huntington’s disease. Cdc37, a co-chaperone that recruits a number of kinases to the Hsp90 complex for stabilization and folding, has been studied in the context of cancer. While Cdc37 has been widely studied as a co-chaperone of Hsp90, it is also a chaperone in its own right. Our work has shown that Cdc37 can stabilize tau and transactive response DNA-binding protein (TDP-43), which are proteins involved in AD, ALS, and other neurological disorders. Depletion of Cdc37 can lead to clearance of TDP-43 protein via autophagy. The Hsp90–Cdc37 complex has also been shown to regulate ULK1, a kinase that plays an integral role in autophagy. Additionally, a number of kinases including Akt, p38, and inositol-requiring enzyme 1, which are clients of Cdc37, have also been shown to regulate autophagy. Evidence for the role of Cdc37 in autophagy is starting to emerge, and understanding its function in autophagy in the context of neurodegenerative diseases may lead to its establishment as a drug target for clearance of toxic aggregates in AD and ALS.