RRC ID 63054
Author Liu EA, Schultz ML, Mochida C, Chung C, Paulson HL, Lieberman AP.
Title Fbxo2 mediates clearance of damaged lysosomes and modifies neurodegeneration in the Niemann-Pick C brain.
Journal JCI Insight
Abstract 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 examined LMP and lysophagy in Niemann-Pick type C (NPC) disease, an autosomal recessive disorder characterized by the accumulation of unesterified cholesterol within late endosomes and lysosomes, leading to neurodegeneration and early death. We demonstrated that NPC human fibroblasts show enhanced sensitivity to lysosomal damage as a consequence of lipid storage. Moreover, we described a role for the glycan-binding F-box protein 2 (Fbxo2) in CNS lysophagy. Fbxo2 functions as a component of the S phase kinase-associated protein 1-cullin 1-F-box protein (SKP1-CUL1-SCF) ubiquitin ligase complex. Loss of Fbxo2 in mouse primary cortical cultures delayed clearance of damaged lysosomes and decreased viability after lysosomal damage. Moreover, Fbxo2 deficiency in a mouse model of NPC exacerbated deficits in motor function, enhanced neurodegeneration, and reduced survival. Collectively, our data identified a role for Fbxo2 in CNS lysophagy and establish its functional importance in NPC.
Volume 5(20)
Published 2020-10-15
DOI 10.1172/jci.insight.136676
PII 136676
PMID 32931479
PMC PMC7605537
MeSH Autophagy / genetics Brain / metabolism* Brain / pathology Cell Cycle Proteins / genetics* Cell Membrane Permeability Cholesterol / metabolism Endosomes / genetics F-Box Proteins / genetics* Fibroblasts / metabolism Fibroblasts / pathology Humans Lysosomes / genetics Macroautophagy / genetics* Nerve Degeneration / genetics* Nerve Degeneration / pathology Nerve Tissue Proteins / genetics* Niemann-Pick Disease, Type C / genetics* Niemann-Pick Disease, Type C / pathology SKP Cullin F-Box Protein Ligases / genetics
IF 6.205
Human and Animal Cells Atg5^(+/+)MEF(RCB2710) Atg5^(-/-)MEF(RCB2711)