(From left) Mauricio Torres, PhD, and Ling Qi, PhD
Researchers from the University of Virginia have uncovered a critical role for the SEL1L-HRD1 complex in preventing neurodegeneration in Purkinje cells—a type of neuron crucial for motor coordination. The findings, published in JCI Insight, provide new insights into the mechanisms of cerebellar ataxia, a disorder that severely affects balance and coordination.
“Our study provides the first direct evidence that the SEL1L-HRD1 ERAD pathway is essential in Purkinje cells to prevent neurodegeneration and motor impairment,” said Mauricio Torres, PhD, first author and research scientist in the Department of Molecular Physiology and Biological Physics at UVA.
Cerebellar ataxia, often caused by Purkinje cell degeneration, is a debilitating condition impacting motor skills and fine coordination. Despite known genetic risk factors, the role of the endoplasmic reticulum-associated degradation (ERAD) pathway—responsible for eliminating misfolded proteins—in the development of cerebellar ataxia has remained unclear. This new research highlights the SEL1L-HRD1 ERAD complex as essential for Purkinje cell health and motor function.
Using a mouse model with Purkinje cell-specific SEL1L deficiency, researchers demonstrated that the loss of SEL1L leads to progressive motor impairment and Purkinje cell death beginning at 9 weeks of age. Advanced imaging techniques revealed altered ER homeostasis and neuroinflammation, including astrocyte and microglial activation, which were correlated with motor dysfunction. These findings underscore the importance of ERAD in maintaining neuronal health and preventing neurodegenerative processes.
“This opens up new avenues for understanding the cellular mechanisms underlying cerebellar ataxia and could lead to potential therapeutic targets for patients suffering from this condition.” said Ling Qi, PhD, senior author and professor in Department of Molecular Physiology and Biological Physics at UVA.
The study’s results align with previous findings in humans and dogs carrying SEL1L variants that exhibit similar ataxia symptoms, suggesting a conserved role across species. Future research aims to further investigate ERAD-specific substrates in Purkinje cells and their involvement in ataxia and neuroinflammation
Filed Under: Research