A critical response to lysosomal membrane permeabilization (LMP) is the clearance of damaged lysosomes through a selective form of macroautophagy known as lysophagy. Although regulators of this process are emerging, whether organ and cell specific components contribute to the control of lysophagy remains incompletely understood. Here, we examine LMP and lysophagy in Niemann-Pick type C disease (NPC), an autosomal recessive disorder characterized by the accumulation of unesterified cholesterol within late endosomes and lysosomes, leading to neurodegeneration and early death. We demonstrate that NPC patient fibroblasts show enhanced sensitivity to lysosomal damage as a consequence of lipid storage. Moreover, we describe a role for the glycan binding F-box protein Fbxo2 in CNS lysophagy. Fbxo2 functions as a component of the SCF ubiquitin ligase complex. Loss of Fbxo2 in mouse primary cortical cultures delays clearance of damaged lysosomes and decreases viability following lysosomal damage. Moreover, Fbxo2 deficiency in a mouse model of NPC exacerbates deficits in motor function, enhances neurodegeneration, and reduces survival. Collectively, our data identify a role for Fbxo2 in CNS lysophagy and establish its functional importance in NPC.


Elaine A. Liu, Mark L. Schultz, Chisaki Mochida, Chan Chung, Henry L. Paulson, Andrew P. Lieberman


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