Inhibition of cathepsin B blocks amyloidogenesis in the mouse models of neurological lysosomal diseases mucopolysaccharidosis type IIIC and sialidosis

Abstract

Neuronal accumulation of amyloid aggregates is a hallmark of brain pathology in neurological lysosomal storage diseases (LSDs) including mucopolysaccharidoses (MPS), however, the molecular mechanism underlaying this pathology has not been understood. We demonstrate that elevated lysosomal cathepsin B (CTSB) levels and CTSB leakage to the cytoplasm triggers amyloidogenesis in two neurological LSDs. CTSB levels were elevated 3-5-fold in the cortices of mouse models of MPS IIIC (Hgsnat-Geo and HgsnatP304L) and sialidosis (Neu1{Delta}Ex3), as well as in cortical samples of MPS I, IIIA, IIIC and IIID patients. CTSB was found in the cytoplasm of pyramidal layer IV-V cortical neurons containing Thioflavin-S-positive, {beta}-amyloid-positive aggregates consistent with pro-senile phenotype. In contrast, CTSB-deficient MPS IIIC (HgsnatP304L/Ctsb-/-) mice as well as HgsnatP304L and Neu1{Delta}Ex3 mice chronically treated with irreversible brain-penetrable CTSB inhibitor, E64, showed a drastic reduction of neuronal Thioflavin-S-positive/APP-positive deposits. Neurons of HgsnatP304L/Ctsb-/- mice and E64-treated HgsnatP304L mice also showed reduced levels of P62/LC3-positive puncta, GM2 ganglioside and misfolded subunit C of mitochondrial ATP synthase (SCMAS) consistent with restored autophagy. E64 treatment also rescued hyperactivity and reduced anxiety in HgsnatP304L mice implying that CTSB may become a novel pharmacological target for MPS III and similar LSDs.