Purkinje cell–specific deficiency in SEL1L-HRD1 endoplasmic reticulum–associated degradation causes progressive cerebellar ataxia in mice
Mauricio Torres, Brent Pederson, Hui Wang, Liangguang Leo Lin, Huilun Helen Wang, Amara Bugarin-Lapuz, Zhen Zhao, Ling Qi
Mauricio Torres, Brent Pederson, Hui Wang, Liangguang Leo Lin, Huilun Helen Wang, Amara Bugarin-Lapuz, Zhen Zhao, Ling Qi
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Research Article Neuroscience

Purkinje cell–specific deficiency in SEL1L-HRD1 endoplasmic reticulum–associated degradation causes progressive cerebellar ataxia in mice

Abstract

Recent studies have identified multiple genetic variants of SEL1L-HRD1 endoplasmic reticulum–associated degradation (ERAD) in humans with neurodevelopmental disorders and locomotor dysfunctions, including ataxia. However, the relevance and importance of SEL1L-HRD1 ERAD in the pathogenesis of ataxia remain unexplored. Here, we showed that SEL1L deficiency in Purkinje cells leads to early-onset progressive cerebellar ataxia with progressive loss of Purkinje cells with age. Mice with Purkinje cell–specific deletion of SEL1L (Sel1LPcp2Cre) exhibited motor dysfunction beginning around 9 weeks of age. Transmission electron microscopy analysis revealed dilated ER and fragmented nuclei in Purkinje cells of adult Sel1LPcp2Cre mice, indicative of altered ER homeostasis and cell death. Finally, loss of Purkinje cells was associated with a secondary neurodegeneration of granular cells, as well as robust activation of astrocytes and proliferation of microglia, in the cerebellums of Sel1LPcp2Cre mice. These data demonstrate the pathophysiological importance of SEL1L-HRD1 ERAD in Purkinje cells in the pathogenesis of cerebellar ataxia.

Authors

Mauricio Torres, Brent Pederson, Hui Wang, Liangguang Leo Lin, Huilun Helen Wang, Amara Bugarin-Lapuz, Zhen Zhao, Ling Qi

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Figure 2

Sel1LPcp2Cre-KO mice exhibit progressive cerebellar ataxia.

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Sel1LPcp2Cre-KO mice exhibit progressive cerebellar ataxia. (A) Represe...
(A) Representative images of paw prints from 6-, 12-, and 22-week-old mice showing gait analysis for Sel1Lf/f and Sel1LPcp-2 mice. The gray and red arrows indicate forelimb and hindlimb, respectively. Lines between gray and red arrows indicate distance between 2 limbs. (B) Cartoon schematic of the gait analysis. (C) Quantitation of gait analysis of 6- to 22-week-old littermates of both sexes (n = 8 mice per group). (D) Representative images of balance beam test from 6- and 22-week-old mice. (E) Quantitation of balance beam test from mice at 6, 12, 18, and 22 weeks of ages (n = 8 mice per group). (F) Representative images of hindlimb clasping of 12- and 22-week-old mice. (G) Quantification of hindlimb clasping from mice at 6, 12,18, and 22 weeks of age (n = 8 mice per group). Data are shown as the mean ± SEM. ***P < 0.001, ****P < 0.0001 by 2-way ANOVA followed by Bonferroni’s multiple comparisons test (C, E, and G). Scale bar: 1 cm (A).