2024 Alzheimer's Association Research Grant to Promote Diversity (AARG-D)

Exploring the role of SEL1L-HRD1 ERAD in Alzheimer's Disease

How do misfolded proteins contribute to Alzheimer’s progression?

Ling Qi, Ph.D.
University of Virginia
Charlottesville, VA - United States

Background

In healthy cells, a specialized structure called the endoplasmic reticulum (ER) helps produce and fold proteins correctly. During aging and in Alzheimer’s, the ER becomes damaged, and cells are no longer able to repair damaged or misfolded proteins. In Alzheimer’s, these damaged and misfolded proteins accumulate inside nerve cells, leading to nerve cell stress and death. 

The accumulation of misfolded proteins in cells triggers a response pathway called ER-associated degradation (ERAD), which acts to quickly break up the misfolded proteins. This process involves many steps and relies on a specific protein called SEL1L to facilitate ERAD. In preliminary studies, Dr. Ling Qi and colleagues have shown that SEL1L levels are decreased in Alzheimer’s brains. However, the impact of SEL1L loss on ERAD in Alzheimer’s is still unknown.

Research Plan

Building on their initial findings, Dr. Qi and team will study the role of SEL1L in ERAD and its impact on Alzheimer’s progression. To do this, they will measure the levels of misfolded protein in the brains of cognitively unimpaired mice that either do or do not have SEL1L. Next, the researchers will measure cognitive function in genetically engineered Alzheimer’s-like mice that develop amyloid plaques or tau tangles (two of the hallmark brain changes in Alzheimer’s) and either do or do not have SEL1L.

Impact

The results of this study may shed new light on the mechanisms by which misfolded proteins accumulate in nerve cells in Alzheimer’s. If successful, the findings could lead to new therapeutic approaches to target this process as a means of slowing the disease progression.