Reference - Detail
| 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 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 8 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | Atg5^(+/+)MEF(RCB2710) Atg5^(-/-)MEF(RCB2711) |