Dr. Shauna Yuan

Medical School
Twin Cities
Project Title: 
Mechanisms of GWAS Risk Variant in Development of Alzheimer's Disease

Alzheimer’s disease (AD) and other types of tauopathies are proteinopathies. The unfolded protein response (UPR), which is a cellular response to remediate proteinopathy in the endoplasmic reticulum (ER), has been observed in post-mortem brains in several neurodegenerative diseases. Dysregulation of the ER stress response is suggested also by genetic evidence. Single nucleotide polymorphisms (SNPs) associated with increased risk for tauopathy were identified by multiple large Genome-Wide Association Studies (GWAS) for PERK (Eukaryotic translation initiation factor 2-alpha kinase 3). PERK acts as one of the sensors and responders for ER stress, regulating a coordinated cellular response to maintain protein quality and to resolve proteostatic stress due to misfolded proteins. The integrity of the UPR when faced with ER stress must be kept intact to maintain the integrity of the proteome. Alterations of these fundamental mechanisms will result in cellular demise and degeneration. Although the tauopathy-related PERK risk variant is found in about 30% of the population, how the SNPs affect the performance of the UPR is not clear. Nor do we yet know if the carriers of the risk SNPs can alter their UPR response through pharmacological interventions. One of goals of this research is to understand how the genetic variant of PERK causes dysregulation of PERK and the unfolded protein response.

Project Investigators

Marcus Phan
Avinash Singh
Dr. Shauna Yuan
Ying Zhang
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