Cln1-mutations suppress Rab7-RILP interaction and impair autophagy contributing to neuropathology in a mouse model of INCL

• Published in: Journal of inherited metabolic disease 2020-04, Vol.43 (5), p.1082-1101
• Main Authors: Sarkar, Chinmoy, Sadhukhan, Tamal, Bagh, Maria B., Appu, Abhilash P., Chandra, Goutam, Mondal, Avisek, Saha, Arjun, Mukherjee, Anil B.
• Format: Article
• Language: English
• ISSN: 0141-8955; 1573-2665
• DOI: 10.1002/jimd.12242

Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating neurodegenerative lysosomal storage disease (LSD) caused by inactivating mutations in the CLN1 gene. CLN1 encodes palmitoyl-protein thioesterase-1 (PPT1), a lysosomal enzyme that catalyzes the deacylation of S-palmitoylated proteins to facilitate their degradation and clearance by lysosomal hydrolases. Despite the discovery more than two decades ago that CLN1 mutations causing PPT1-deficiency underlies INCL, the precise molecular mechanism(s) of pathogenesis has remained elusive. Here we report that autophagy is dysregulated in Cln1 −/− mice, which mimic INCL and in postmortem brain tissues as well as cultured fibroblasts from INCL patients. Moreover, Rab7, a small GTPase, critical for autophagosome-lysosome fusion, requires S-palmitoylation for trafficking to the late endosomal/lysosomal membrane where it interacts with RILP (Rab-interacting lysosomal protein), essential for autophagosome-lysosome fusion. Notably, Ppt1-deficiency in Cln1 −/− mice, dysregulated Rab7-RILP interaction and preventing autophagosome-lysosome fusion, which impaired degradative functions of the autolysosome leading to INCL pathogenesis. Importantly, treatment of Cln1 −/− mice with a brain-penetrant, PPT1-mimetic, small molecule, N-tert (Butyl)hydroxylamine (NtBuHA), ameliorated this defect. Our findings reveal a previously unrecognized role of CLN1 /PPT1 in autophagy and suggest that small molecules functionally mimicking Ppt1 may have therapeutic implications.