Altered lipid homeostasis is associated with cerebellar neurodegeneration in SNX14 deficiency
Yijing Zhou, Vanessa B. Sanchez, Peining Xu, Thomas Roule, Marco Flores-Mendez, Brianna Ciesielski, Donna Yoo, Hiab Teshome, Teresa Jimenez, Shibo Liu, Mike Henne, Tim O’Brien, Ye He, Clementina Mesaros, Naiara Akizu
Yijing Zhou, Vanessa B. Sanchez, Peining Xu, Thomas Roule, Marco Flores-Mendez, Brianna Ciesielski, Donna Yoo, Hiab Teshome, Teresa Jimenez, Shibo Liu, Mike Henne, Tim O’Brien, Ye He, Clementina Mesaros, Naiara Akizu
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Research Article Neuroscience

Altered lipid homeostasis is associated with cerebellar neurodegeneration in SNX14 deficiency

Abstract

Dysregulated lipid homeostasis is emerging as a potential cause of neurodegenerative disorders. However, evidence of errors in lipid homeostasis as a pathogenic mechanism of neurodegeneration remains limited. Here, we show that cerebellar neurodegeneration caused by Sorting Nexin 14 (SNX14) deficiency is associated with lipid homeostasis defects. Recent studies indicate that SNX14 is an interorganelle lipid transfer protein that regulates lipid transport, lipid droplet (LD) biogenesis, and fatty acid desaturation, suggesting that human SNX14 deficiency belongs to an expanding class of cerebellar neurodegenerative disorders caused by altered cellular lipid homeostasis. To test this hypothesis, we generated a mouse model that recapitulates human SNX14 deficiency at a genetic and phenotypic level. We demonstrate that cerebellar Purkinje cells (PCs) are selectively vulnerable to SNX14 deficiency while forebrain regions preserve their neuronal content. Ultrastructure and lipidomic studies reveal widespread lipid storage and metabolism defects in SNX14-deficient mice. However, predegenerating SNX14-deficient cerebella show a unique accumulation of acylcarnitines and depletion of triglycerides. Furthermore, defects in LD content and telolysosome enlargement in predegenerating PCs suggest lipotoxicity as a pathogenic mechanism of SNX14 deficiency. Our work shows a selective cerebellar vulnerability to altered lipid homeostasis and provides a mouse model for future therapeutic studies.

Authors

Yijing Zhou, Vanessa B. Sanchez, Peining Xu, Thomas Roule, Marco Flores-Mendez, Brianna Ciesielski, Donna Yoo, Hiab Teshome, Teresa Jimenez, Shibo Liu, Mike Henne, Tim O’Brien, Ye He, Clementina Mesaros, Naiara Akizu

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Figure 3

SNX14 deficiency causes selective cerebellar degeneration.

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SNX14 deficiency causes selective cerebellar degeneration. (A) Represent...
(A) Representative brain images from WT and KO mice at indicated age shows shrinkage of KO cerebellum (CB) over time. Ruler marks separated by 1 mm. Bar graphs show percentage area of CB or cerebral cortex (CX) relative to the whole brain (WB) in n = 3–5 mice. Two-way ANOVA followed by Šidák’s test. (B) Representative cerebellar sagittal sections immunostained with PC-specific anti-CALB1 antibody reveal progressive loss of PCs in KO mice. Bar graphs show PC linear density (right) and thickness of the molecular layer (left) in the cerebellar lobule III of n = 3–4 mice. Two-way ANOVA followed by Šidák’s test. (C) Representative immunostaining of PCs with anti-CALB1 antibody reveals progressive accumulation of vacuoles in KO mice. (D) Immunostaining of PCs with anti-CALB1 and lysosomes with anti-LAMP1 show enlarged lysosomes in KO mice. Bar graph shows average lysosome size per mouse. n = 3 mice (in WT, 29 PCs and 4,033 lysosomes were counted; in KO, 30 PCs and 3,247 lysosomes were counted). Two-tailed t test. (E and F) Representative immunostaining showing progressive accumulation of astrocytes labeled with anti-GFAP (E) and microglia with anti-IBA1 (F) in degenerating KO cerebella (base of lobules III and IV). (G) Coronal sections of cerebral cortices immunostained with anti-NeuN do not show differences between WT and KO mice. Bar graphs show percentage thickness occupied by each cortical layers (I–VI) in 4–5 cortical regions of 2 mice per genotype and age. Two-way ANOVA followed by Šidák’s test. In all graphs, data represent mean ± SEM. *P < 0.05, **P < 0.01, ****P < 0.0001. Scale bars: 1 mm, 5 μm, 75 μm.