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.

中文翻译：

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Cln1 突变抑制 Rab7-RILP 相互作用并损害自噬，导致婴儿神经元蜡质脂褐质沉着症小鼠模型的神经病理学。


婴儿神经元蜡样质脂褐质沉积症 (INCL) 是一种毁灭性的神经退行性溶酶体贮积病 (LSD)，由CLN1基因失活突变引起。 CLN1编码棕榈酰蛋白硫酯酶-1 (PPT1)，这是一种溶酶体酶，可催化 S-棕榈酰化蛋白的脱酰化，以促进其被溶酶体水解酶降解和清除。尽管二十多年前就发现导致 PPT1 缺陷的CLN1突变是 INCL 的基础，但发病机制的精确分子机制仍然难以捉摸。在这里，我们报告说，在模仿 INCL 的Cln1 ^−/−小鼠、死后脑组织以及 INCL 患者培养的成纤维细胞中，自噬失调。此外，Rab7 是一种小 GTP 酶，对自噬体-溶酶体融合至关重要，需要 S-棕榈酰化才能运输到晚期内体/溶酶体膜，在此处与 Rab 相互作用溶酶体蛋白 (RILP) 相互作用，而 Rab 对于自噬体-溶酶体融合至关重要。值得注意的是， Cln1 ^-/−小鼠中的 PPT1 缺陷，导致 Rab7-RILP 相互作用失调并阻止自噬体-溶酶体融合，从而损害自溶酶体的降解功能，导致 INCL 发病机制。重要的是，用脑渗透性PPT1模拟小分子N-叔丁基羟胺(NtBuHA)治疗Cln1 ^−/−小鼠，改善了这一缺陷。我们的研究结果揭示了CLN1 /PPT1 在自噬中先前未被认识的作用，并表明功能上模仿 PPT1 的小分子可能具有治疗意义。