PPT1-deficiency impairs maturation and activity of lysosomal cathepsin D contributing to INCL pathogenesis

Wednesday, October 26, 2011 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center	NICHD	NEURO/BEHAV/SENSYS-6

* FARE Award Winner

Authors

• G Chandra
• A Saha
• MR Moralle
• Z Zhang
• C Sarkar
• S Peng
• AB Mukherjee

Abstract

Neuronal ceroid lipofuscinoses (NCLs) constitute a group of common (1 in 12,500 births) childhood neurodegenerative lysosomal storage disorders. Mutations in 8 different genes underlie various types of NCLs. 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 by lysosomal hydrolases. Although a suggested mechanism of INCL pathogenesis is that PPT1-deficiency causes abnormal accumulation of s-acylated proteins (constituent of ceroid) in lysosomes because these lipid-modified proteins are refractory to degradation by lysosomal proteases and consequently, leads to INCL pathogenesis. However, the precise mechanism of INCL pathogenesis remains poorly understood. We previously reported that excessive ER- and oxidative-stress contribute to INCL pathogenesis. We report here that oxidative-stress mediates overexpression of lysosomal cathepsin D (CTSD) via elevation of a oxidative stress-sensitive transcription factor, CEBP-∂. Interestingly, while CTSD-mRNA and protein expression is elevated in the brain of Ppt1-knockout (Ppt1-KO) mice, the maturation and activity of CTSD were impaired. We propose that this abnormality in CTSD inhibits degradation of s-acylated proteins leading to the accumulation of ceroid in lysosomes contributing to INCL pathogenesis.

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