Investigators: Henry Paulson, Lisa Marie Sharkey, Geoffrey G. Murphy
Funding: National Institute of Neurological Disorders and Stroke, 2015-2017 (1 R21 NS 093469 01)
Ubiquilin2 (UBQLN2) is one of two closely related ubiquilin proteins recently implicated in a wide range of neurodegenerative diseases, including Alzheimer's disease, Lewy Body Dementia, Frontotemporal Dementia and Huntington's disease. Mutations in the UBQLN2 gene also directly cause an inherited fatal neurodegenerative disorder that spans the Frontotemporal Dementia/Amyotrophic Lateral Sclerosis (FTD/ALS) spectrum and is associated with accumulation of the RNA binding protein TDP43. Ubiquilins are believed to normally help maintain neuronal protein homeostasis, but their function in neurological health and in disease is still poorly understood. This project leverages a valuable new research tool – transgenic mouse lines expressing wild-type or pathogenic (mutant) UBQLN2 – to advance scientific understanding of the role of ubiquilins in a wide variety of neurodegenerative diseases, ranging from more common to rarer diseases. These new models are expected to accelerate discoveries about both the normal role of UBQLN2 in neurodegenerative proteinopathies and the mechanism by which mutations in this quality control protein cause FTD/ALS. Specifically, the project aims to define the neuropathological features in transgenic mice expressing wild-type or mutant UBQLN2, and to assess motor, behavioral, and electrophysiological changes in UBQLN2 transgenic mice. This work is intended to answer fundamental questions about normal and mutant UQBLN2 behavior and, more broadly, about the role of ubiquilins in brain health and disease, that could have important ramifications for therapeutic strategies.