Fig. 2.

Strategies to combat α-synuclein aggregation by the downstream enhancement of autophagy. Oligomeric and mutant forms of α-synuclein impair CMA functioning in PD, which may be alleviated by the recently developed retinoic acid alpha receptor inhibitors (RA-α-R inhibitors). The intralysosomal presence of α-synuclein further results in impaired GCase functioning, while it blocks the transport of GCase from the ER to the lysosome. Together, these processes lead to reduced GCase hydrolase activity and lysosomal dysfunction in PD. Small-molecule GCase chaperones, including ambroxol and isofagomine, specifically target the misfolded GCase trapped in the ER to increase trafficking of GCase to lysosomes. Acidic nanoparticles improve lysosomal functioning by lowering the pH within the lysosomal lumen