UVA Researchers Identify Genetic Genetic Variant That Causes Cerebellar Ataxia

March 13, 2024 by

Leo Liangguang UVA

Liangguang Leo Lin, PhD

Endoplasmic reticulum-associated degradation (ERAD) is an essential protein quality control machinery that maintains protein homeostasis and human health. The Qi laboratory in the Department of Molecular of Molecular Physiology and Biological Physics at UVA recently identified human variants of the SEL1L and HRD1 proteins (two key ERAD components) in patients with neurodevelopmental disorders with onset infancy syndrome. Learn more about this research here.

The group has now teamed up with the Sun laboratory in the Department of Pharmacology to focus on another variant of SEL1L, initially identified in 2012 in Finnish Hounds with cerebellar ataxia; however, whether this variant causes ataxia in mammals remained unclear. In a recent study published in Nature Communications titled “SEL1L-HRD1 interaction is required to form a functional HRD1 ERAD complex,” a team led by Liangguang Leo Lin, PhD, in the Qi lab has identified the disease-causality of this variant in the cerebellar ataxia.

Using mouse models, the team has revealed that this specific SEL1L variant causes ERAD dysfunction, resulting in developmental delays and early-onset, non-progressive cerebellar ataxia in mice. This finding is crucial in understanding the pathological implications of the variant in mammalian neurological development.

The study also incorporated biochemical and AI-protein structural analyses, determining that this SEL1L variant disrupts the SEL1L-HRD1 interaction. Proteomic screening further reveals this interaction is essential for forming a functional HRD1 ERAD complex as SEL1L is necessary to bring other important components into HRD1 complex.

This research not only establishes the disease relevance of SEL1L-HRD1 ERAD pathway, but also provides deeper insight into the mechanisms involved in forming a functional HRD1 ERAD complex. Notably, the study was recognized as one of the 50 best recent publications in the field spanning “From molecules and cells to organisms” by Nature Communications.

This study was supported by National Institutes of Health RF1NS122060, R01DK128077, R01DK132068, R01DK120047, R01DK120330, R35GM130292 and National Ataxia Foundation Post- and Pre-doctoral Fellowship. Other authors contributing to this groundbreaking research including Huilun Helen Wang, PhD, Brent Pederson, Xiaoqiong Wei, PhD, Mauricio Torres, PhD, You Lu, PhD, You Lu, PhD, Zexin Jason Li, Xiaodan Liu, PhD, Hancheng Mao, Hui Wang, PhD, Linyao Zhou, and Zhen Zhao, PhD.

Filed Under: Research