Fig. 9: Schematic model of how CRBN modulates pathological forms of α-SYN.
From: CRBN modulates synuclein fibrillation via degradation of DNAJB1 in mouse model of Parkinson disease
Several insults including oxidative stress can lead to an increase in the aggregation of α-SYN. DJ1 is a master regulator of the non-pathological states of α-SYN. Recruitment and degradation of DJ1 by CRBN decreases the availability of DJ1. CRBN-mediated modulation of chaperone activity of DJ1 disturbs the homeostatic balance, eventually triggering or promoting PD. Hence, inhibition of CRBN to recruit DJ1 may prevent the formation of oligomeric α-SYN by maintaining a non-phosphorylated and non-pathological pool of α-SYN. PDB ID for the 3D structure of α-SYN PFF is 2NOA, for α-SYN monomer is 1XQ8, for CRBN is 4CI3, and for DJ1 the 3D structure was modeled by I-TASSER server33. Structure of tetrapeptide inhibitor was drawn using ChemDraw software.
