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 3

Purkinje cell SEL1L deletion leads to Purkinje cell loss and degeneration of the granular layer.

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Purkinje cell SEL1L deletion leads to Purkinje cell loss and degeneratio...
(A–C) H&E-stained sagittal sections of the cerebellum from 5- (A), 12- (B), and 20-week-old mice (C). White arrowheads indicate Purkinje cells. (D) Quantitation of Purkinje cell density in H&E-stained sagittal sections of the cerebellums of mice at 5, 12, and 20 weeks of age (n = 6 mice per group). (E) Quantitation of granular cells in an area of 25 μm × 25 μm on the granular layer of the cerebellum (n = 6 mice per group). (F) Representative images of the molecular layer at 5 and 20 weeks of age, with quantitation of molecular layer thickness shown in G (n = 6 mice per group). Data are shown as the mean ± SEM. ****P < 0.0001 by 2-way ANOVA followed by Bonferroni’s multiple comparisons test (D, E, and G). Scale bar: 0.5 mm (A–C, first column); 20 μm (C, fourth column); 50 μm (A–C, third column, and F); 100 μm (A–C, second column).