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Cln1 ‐mutations suppress Rab7‐RILP interaction and impair autophagy contributing to neuropathology in a mouse model of infantile neuronal ceroid lipofuscinosis
Author(s) -
Sarkar Chinmoy,
Sadhukhan Tamal,
Bagh Maria B.,
Appu Abhilash P.,
Chandra Goutam,
Mondal Avisek,
Saha Arjun,
Mukherjee Anil B.
Publication year - 2020
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1002/jimd.12242
Subject(s) - autophagy , autophagosome , microbiology and biotechnology , lysosome , batten disease , neuronal ceroid lipofuscinosis , biology , rab , lysosomal storage disease , neurodegeneration , endosome , chemistry , biochemistry , gtpase , intracellular , medicine , gene , apoptosis , disease , pathology , enzyme
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 Rab‐interacting lysosomal protein (RILP), 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.