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Despite the discovery more than two decades ago that <jats:italic>CLN1<\/jats:italic> mutations causing PPT1\u2010deficiency underlies INCL, the precise molecular mechanism(s) of pathogenesis has remained elusive. Here, we report that autophagy is dysregulated in <jats:italic>Cln1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> 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\u2010lysosome fusion, requires S\u2010palmitoylation for trafficking to the late endosomal\/lysosomal membrane where it interacts with Rab\u2010interacting lysosomal protein (RILP), essential for autophagosome\u2010lysosome fusion. Notably, PPT1\u2010deficiency in <jats:italic>Cln1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice, dysregulated Rab7\u2010RILP interaction and preventing autophagosome\u2010lysosome fusion, which impaired degradative functions of the autolysosome leading to INCL pathogenesis. Importantly, treatment of <jats:italic>Cln1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice with a brain\u2010penetrant, PPT1\u2010mimetic, small molecule, N\u2010tert (butyl)hydroxylamine (NtBuHA), ameliorated this defect. Our findings reveal a previously unrecognized role of <jats:italic>CLN1<\/jats:italic>\/PPT1 in autophagy and suggest that small molecules functionally mimicking PPT1 may have therapeutic implications.<\/jats:p>","DOI":"10.1002\/jimd.12242","type":"journal-article","created":{"date-parts":[[2020,4,12]],"date-time":"2020-04-12T08:53:57Z","timestamp":1586681637000},"page":"1082-1101","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["<i>Cln1<\/i>\u2010mutations suppress <scp>Rab7\u2010RILP<\/scp> interaction and impair autophagy contributing to neuropathology in a mouse model of infantile neuronal ceroid lipofuscinosis"],"prefix":"10.1002","volume":"43","author":[{"given":"Chinmoy","family":"Sarkar","sequence":"first","affiliation":[{"name":"Section on Developmental Genetics, Division of Translational Medicine Eunice Kennedy Shriver National Institute of Child Health and Human Development  Bethesda Maryland 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