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Publication
Purkinje cell-specific deficiency in SEL1L-hrd1 endoplasmic reticulum-associated
degradation causes progressive cerebellar ataxia in mice.
Authors Torres M, Pederson B, Wang H, Lin LL, Wang HH, Bugarin-Lapuz A, Zhao Z, Qi L
Submitted By Submitted Externally on 2/7/2025
Status Published
Journal JCI insight
Year 2024
Date Published 11/1/2024
Volume : Pages 9 : Not Specified
PubMed Reference 39352758
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.




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