Chaperone-Based Therapies for Disease Modification in Parkinson’s Disease

Figure 1

Proposed role of molecular and small molecule chaperones in proteostasis. At baseline, Hsp90 is bound to HSF-1, maintaining its inactive state. In the presence of proteotoxic stress, or the addition of Hsp90 inhibitors (i.e., geldanamycin, 17-AAG, and SNX compounds), active HSF-1 dissociates from Hsp90 and translocates into the nucleus where it induces Hsp70 expression. Inducible Hsp70 family members direct proteasomal degradation through a pathway mediated by CHIP, Parkin, and other E3 ligases. This process is inhibited by BAG family members and promoted by small molecule HSF-1 activators including celastrol and carbenoxolone. In response to proteotoxic stress, chaperones also direct misfolded proteins for degradation via the autophagy-lysosome system, through interactions with various cochaperones (chaperone-mediated autophagy). Chaperone/cochaperone complexes can also function to disaggregate already formed protein aggregates. The pharmacological chaperones, ambroxol, and isofagomine increase glucocerebrosidase (GCase) activity in the lysosome to further promote the process of chaperone-mediated autophagy. Chaperone functions within the endoplasmic reticulum and mitochondria are regulated by the specific members of the Hsp70 family, HSPA5 and HSPA9, respectively.