Purkinje cell–specific deficiency in SEL1L-HRD1 endoplasmic reticulum–associated degradation causes progressive cerebellar ataxia in mice
Mauricio Torres, … , Zhen Zhao, Ling Qi
Mauricio Torres, … , Zhen Zhao, Ling Qi
Published October 1, 2024
Citation Information: JCI Insight. 2024;9(21):e174725. https://doi.org/10.1172/jci.insight.174725.
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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 5

ER expansion and Purkinje cell neurodegeneration in Sel1LPcp2Cre mice.

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ER expansion and Purkinje cell neurodegeneration in Sel1LPcp2Cre mice. (...
(A) Representative TEM images of WT and Sel1L-deficient Purkinje cells (highlighted by red dotted lines) from 5-week-old mice. High-magnification images (marked as 1 and 2) show the endoplasmic reticulum (ER; white arrows) in 2 different locations of the cell (n = 3 mice per group). (B) Representative TEM images of WT and Sel1L-deficient Purkinje cells showing fragmentation of the nucleus (N) and ER expansion at 9 weeks of age (n = 3 mice per group). (C) Representative TEM images of Sel1L-deficient Purkinje cells showing ER expansion and accumulation of electrodense structures (blue arrows) at 9 weeks of age (n = 3 mice per group). (D) Quantification of luminal ER width in TEM images of mice at 5 and 9 weeks of age (250–300 measurements from 10 cells, n = 3 mice per group). (E) Representative fluorescence images of TUNEL-labeled and DAPI-stained sagittal cerebellar sections of Sel1Lf/f and Sel1LPcp2 mice at 9 weeks of age. Higher-magnification images of selected areas are showed to the left. White arrows indicate TUNEL-positive labeled nuclei. (F) Quantitation of TUNEL-positive cells in the cerebellum of 9-week-old mice (n = 3 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 (D) and t test (F). Scale bar: 0.5 μm (A, second column; B, second column, images marked as 2; and C, second column); 1 μm (B, second column, images marked as 1); 2 μm (A–C, first column); 50 μm (E, third and fourth image); 100 μm (E, first and second image).