Impaired lysosomal maturation of pro‐cathepsin D to active cathepsin D in a childhood neurodegenerative lysosomal storage disease

Abstract

Neuronal ceroid lipofuscinoses (NCLs) constitute a group of childhood neurodegenerative lysosomal storage disorders. The infantile NCL (INCL), the most lethal among all NCLs, is caused by inactivating mutations in the palmitoyl‐protein thioesterase‐1 (PPT1) gene. PPT1 is a lysosomal enzyme that catalyzes the cleavage of thioester linkage in palmitoylated (S‐acylated) proteins facilitating their degradation. Although a suggested mechanism of INCL pathogenesis is that PPT1‐deficiency causes abnormal accumulation of S‐acylated proteins in lysosomes, the precise molecular mechanism remains poorly understood. We report here that oxidative‐stress mediates overexpression of lysosomal procathepsin D (pro‐CTSD) via increased production of an oxidative stress‐sensitive transcription factor, CEBP‐∂. Interestingly, while pro‐CTSD‐mRNA and protein expression is elevated in the brain of Ppt1‐knockout mice, the maturation and activity of lysosomal CTSD were impaired. Our results suggest that due to the increase in lysosomal pH in PPT1‐deficient cells the activity of cathepsin L, which is required for cathepsin D processing, is disrupted and consequently, both the levels of mature cathepsin D and its activity are impaired. We propose that this abnormality impairs the degradation of lysosomal cargo, which contributes to INCL pathogenesis. This work was supported by Intramural Research Program of NICHD.