Lack of cathepsin B increases severity in Niemann-Pick disease, type C1 mice

Neurodegeneration is a hallmark of Niemann-Pick disease type C1 (NPC1). One component in the pathology of neurodegeneration is increased lysosomal membrane permeability, especially in microglia. Leakage of lysosomal proteases, such as cathepsin B, into the cytoplasm and ultimately into the interstitial space can lead to activation of apoptosis and neuroinflammation. In line with previous reports showing the involvement of cathepsin B in neurodegeneration and the benefit of inhibiting cathepsin B to prevent neurodegeneration, we tested whether disease severity would be reduced in NPC1 mutant mice devoid of cathepsin B. Contrary to our expectation, the double mutant mice exhibited a more severe disease phenotype as measured by disease severity phenotypic scoring, beam walk latency test and a reduction in life expectancy. This highlights the importance of cathepsin B during postnatal development in the context of NPC1.