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Fbxo2 mediates clearance of damaged lysosomes and modifies neurodegeneration in the Niemann-Pick C brain
Elaine A. Liu, … , Henry L. Paulson, Andrew P. Lieberman
Elaine A. Liu, … , Henry L. Paulson, Andrew P. Lieberman
Published September 15, 2020
Citation Information: JCI Insight. 2020;5(20):e136676. https://doi.org/10.1172/jci.insight.136676.
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Research Article Neuroscience

Fbxo2 mediates clearance of damaged lysosomes and modifies neurodegeneration in the Niemann-Pick C brain

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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.

Authors

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

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Figure 5

Fbxo2 is the most highly expressed glycan-binding F-box protein in the brain.

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Fbxo2 is the most highly expressed glycan-binding F-box protein in the b...
(A) Ctrl patient fibroblasts were pretreated with DMSO or 1 μM MLN7243 for 4 hours and then treated as indicated with 30 μg/mL CHX and 2 mM LLOMe. LAMP-1 levels quantified at the right. (B) Allen Brain Atlas expression data of Fbxo2, Fbxo6, and Fbxo27 in mouse brain. (C) Relative expression of Fbxo2, Fbxo6, and Fbxo27 was determined in the cerebellum, cortex, and brainstem of WT and I1061T mice at 12 weeks by qPCR. N = 4–5 mice per genotype. Data are shown as mean ± SEM from (A) 4 independent experiments. *P ≤ 0.05, ***P ≤ 0.001, ****P ≤ 0.0001 by (A and C) 1-way ANOVA with Tukey’s multiple comparisons [(A) F = 2.803, (C) F = 78.88 (CB), F = 95.66 (CX), F = 128.7 (BS)]. Fbxo2, F-box protein 2; Ctrl, control; CHX, cycloheximide; LLOMe, L-leucyl-L-leucine methyl ester; CB, cerebellum; CX, cortex; BS, brainstem.

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