Azeem Saifee
Research Mentor(s): Lisa Sharkey
Research Mentor School/College/Department: Department of Neurology
Presentation Date: 08/03/2022
Presentation Type: Poster
Poster Number: 34
Session: Session II: 1:30 – 2:20pm
Room: League Ballroom
Authors: Azeem Saifee, Henry Pauslon, MD PhD & Lisa Sharkey, PhD
Abstract
Protein misfolding and subsequent aggregation disrupts normal protein function, and in the nervous system can lead to neurodegenerative disorders such as Alzheimer’s disease, Frontotemporal Dementia, and Huntington’s disease. Within cells, various mechanisms prevent misfolding and facilitate the clearance of misfolded proteins, collectively termed as protein quality control (PQC). Ubiquilins (UBQLN) are a family of conserved ubiquitin adaptor proteins that participate in ubiquitin-dependent PQC. Among them, UBQLN2 is most abundantly expressed in the brain and body and is implicated in several neurodegenerative diseases, including as a direct cause of fatal inherited neurodegenerative disease on the Frontotemporal Dementia/Amyotrophic Lateral Sclerosis (FTD/ALS) spectrum through a mutation. However, the mechanisms underlying its function in health and disease and the interacting proteins that regulate its function remain largely unexplored. Previous studies have shown the interaction of UBQLN2 with a pathogenic huntingtin (HTT) polyglutamine protein in a mouse model of Huntington’s disease. The goal of this study is to determine the effect of mutant UBQLN2 on subcellular localization and function, illuminating the way normal and mutant UBQLN2 behavior differ. Various experiments using brain tissue of this pathogenic HTT mouse model with mutant and wild type UBQLN2 will be conducted to determine the difference in ability of each UBQLN2 to rescue the Huntington pathology and localize in condensates through phase separation within individual neurons in the hippocampus and cerebellum. We hope this research will build our knowledge of UBQLN2 in neurodegenerative pathology and demonstrate potential therapeutic strategies.
