Journal article
Fbxo2 mediates clearance of damaged lysosomes and modifies neurodegeneration in the Niemann-Pick C brain
JCI insight, Vol.5(20), e136676
10/15/2020
DOI: 10.1172/jci.insight.136676
PMCID: PMC7605537
PMID: 32931479
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.
Glycan binding protein Fbxo2 regulates lysophagy in the brain, and its deficiency exacerbates neuronal deficits in a mouse model of Niemann-Pick type C disease.
Details
- Title: Subtitle
- Fbxo2 mediates clearance of damaged lysosomes and modifies neurodegeneration in the Niemann-Pick C brain
- Creators
- Elaine A. Liu - University of MichiganMark L. Schultz - University of Michigan Medical SchoolChisaki Mochida - Yamaguchi UniversityChan Chung - University of Michigan Medical SchoolHenry L. Paulson - University of MichiganAndrew P. Lieberman - University of Michigan Medical School
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.5(20), e136676
- DOI
- 10.1172/jci.insight.136676
- PMID
- 32931479
- PMCID
- PMC7605537
- NLM abbreviation
- JCI Insight
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Publisher
- American Society for Clinical Investigation
- Grant note
- R01 NS063967,T32-GM007863,T32-GM007315,T32 NS007222,R01 NS096785 / U.S. National Institutes of Health
- Language
- English
- Date published
- 10/15/2020
- Academic Unit
- Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics
- Record Identifier
- 9984366280302771
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