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 2

SNX14 deficiency in mice recapitulates motor and behavioral deficits of SCAR20.

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SNX14 deficiency in mice recapitulates motor and behavioral deficits of ...
(A and B) Catwalk analysis shows altered gait of KO mice with a longer stand (A) and shorter swing (B) than WT mice. Data are shown as mean ± SEM of n = 24 WT and n = 18 KO mice. Two-tailed Welch’s t test. (C) Metz ladder rung test shows altered limb placing and coordination of KO males and females. Data are shown as mean foot slip of 5 trials performed in consecutive days ± SEM of n = 10 WT males, n = 7 KO males, n = 12 WT females, and n = 12 KO females. Two-way ANOVA followed by Šidák’s test. (D) Accelerating rotarod reveals defects in motor performance of KO mice in the 9 trials performed over 3 consecutive days. Data are shown as mean latency to fall ± SEM of n = 11 WT males, n = 7 KO males, n = 13 WT females, and n = 11 KO. Two-way ANOVA shows siginficant effect of genotype. (E) KO females show impaired learning rate on accelerating rotarod performance over time (between trial 1 and 9). Data are shown as mean learning rate ± SEM of n = 9 WT males, n = 7 KO males, n = 13 WT females, and n = 10 KO females. Two-way ANOVA followed by Šidák’s test. (F and G) Three-chamber social interaction test showing similar preference for a mouse over an object between WT and KO mice (F) but impaired social novelty preference in KO mice (G). Data are shown as mean ± SEM of n = 24 WT and n = 17 KO. Two-way ANOVA followed by Tukey’s test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.