Genetic and pharmacological evidence implicates cathepsins in Niemann-Pick C cerebellar degeneration

Human Molecular Genetics
Chan ChungAndrew P Lieberman

Abstract

Niemann-Pick C1 (NPC) disease, an autosomal recessive lipid trafficking disorder caused by loss-of-function mutations in the NPC1 gene, is characterized by progressive neurodegeneration resulting in cognitive impairment, ataxia and early death. Little is known about the cellular pathways leading to neuron loss. Here, we studied the effects of diminishing expression of cystatin B, an endogenous inhibitor of cathepsins B, H and L, on the development of NPC neuropathology. We show that decreased expression of cystatin B in patient fibroblasts enhances cathepsin activity. Deletion of the encoding Cstb gene in Npc1-deficient mice resulted in striking deleterious effects, particularly within the cerebellum where diffuse loss of Purkinje cells was observed in young mice. This severe pathology occurred through cell autonomous mechanisms that triggered Purkinje cell death. Moreover, our analyses demonstrated the mislocalization of lysosomal cathepsins within the cytosol of Npc1-deficient Purkinje cells. We provide evidence that this may be a consequence of damage to lysosomal membranes by reactive oxygen species (ROS), leading to the leakage of lysosomal contents that culminates in apoptotic cell death. Consistent with this notion, toxi...Continue Reading

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Citations

Mar 31, 2016·Brain Research·Mark L SchultzAndrew P Lieberman
Dec 12, 2018·The EMBO Journal·Enrique Gabandé-RodríguezMaría Dolores Ledesma
Aug 28, 2019·Journal of Inherited Metabolic Disease·Nina PatelWendy E Heywood
May 6, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Rami A BalloutAlan T Remaley
Oct 15, 2019·Journal of Neurochemistry·Simon Wheeler, Dan J Sillence
Aug 1, 2020·International Journal of Molecular Sciences·Antony CougnouxForbes D Porter
Aug 14, 2020·Neural Regeneration Research·Amanda Phuong Tran, Jerry Silver

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