The amyloid self-assembly inhibitor CLR01 relieves autophagy and ameliorates neuropathology in a severe lysosomal storage disease

Abstract Lysosomal storage diseases (LSDs) are inherited disorders caused by lysosomal deficiencies and characterized by dysfunction of autophagy-lysosomal pathway often associated with neurodegeneration. No cure is currently available to treat neuropathology in LSDs. By studying a mouse model of mucopolysaccharidosis (MPS) type IIIA, one of the most common and severe forms of LSDs, we found that multiple amyloid proteins including α-synuclein, PrP, Tau and amyloid s progressively aggregate in the brain. The amyloid deposits mostly build up in neuronal cell bodies concomitantly with neurodegeneration. Treating MPS-IIIA mice with CLR01, a “molecular tweezer” that acts as a broad-spectrum inhibitor of amyloid protein self-assembly reduced lysosomal enlargement and re-activates autophagy flux. Restoration of autophagy-lysosomal pathway was associated with reduced neuroinflammation and amelioration of memory deficits. Together, these data provide evidence that brain deposition of amyloid proteins plays a gain of neurotoxic function in a severe LSD by affecting autophagy-lysosomal pathway and identify CLR01 as new potent drug candidate for MPS-IIIA and likely for other LSDs.