Targeting Chaperone/Co-Chaperone Interactions with Small Molecules: A Novel Approach to Tackle Neurodegenerative Diseases

Abstract

The dysfunction of the proteostasis network is a molecular hallmark of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Molecular chaperones are a major component of the proteostasis network and maintain cellular homeostasis by folding client proteins, assisting with intracellular transport, and interfering with protein aggregation or degradation. Heat shock protein 70 kDa (Hsp70) and 90 kDa (Hsp90) are two of the most important chaperones whose functions are dependent on ATP hydrolysis and collaboration with their co-chaperones. Numerous studies implicate Hsp70, Hsp90, and their co-chaperones in neurodegenerative diseases. Targeting the specific protein–protein interactions between chaperones and their particular partner co-chaperones with small molecules provides an opportunity to specifically modulate Hsp70 or Hsp90 function for neurodegenerative diseases. Here, we review the roles of co-chaperones in Hsp70 or Hsp90 chaperone cycles, the impacts of co-chaperones in neurodegenerative diseases, and the development of small molecules modulating chaperone/co-chaperone interactions. We also provide a future perspective of drug development targeting chaperone/co-chaperone interactions for neurodegenerative diseases.

Hsp90: From Cellular to Organismal Proteostasis

“…There are other promising small-molecule Hsp90-modulator candidates that have been tested in the context of neurodegenerative disease and heat shock response. One can refer to two excellent recent reviews for details [ 166 , 167 ]. A meta-analysis of the Alzheimer’s disease proteome revealed that the levels of Hsp90 family members is reduced in diseased brains, while most other chaperones and co-chaperones do not show change, with the notable exception of Hsp70, its nucleotide exchange factor BAG3, and neuronal small HSPs, which were found to be upregulated [ 168 ].…”

Protein Misfolding and Aggregation in the Brain: Common Pathogenetic Pathways in Neurodegenerative and Mental Disorders

“…For the diseases associated with impaired protein folding, influencing the activity of chaperone systems may be one of the targets in drug therapy [53], either by altering chaperone gene activity [54] or by acting on chaperones with the molecules that enhance or weaken their function [55]. These therapeutic strategies are being developed for neurodegenerative diseases, among others [54][55][56][57][58].…”