Investigators: Henry Paulson, Sami J. Barmada, Lisa Marie Sharkey, Magdalena Ilieva Ivanova, Brandon Thomas Ruotolo
Funding: National Institute of Neurological Disorders and Stroke, 2016-2021 (9 R01 NS 096785 06)
Mutations in Ubiquilin2 (UBQLN2) were recently identified as a cause of FTD/ALS associated with TDP43 deposition. The involvement of UBQLN2 in ALS/FTD ? and of the broader family of Ubiquilin proteins in a wide variety of neurodegenerative diseases, including TDP43 proteinopathies -- reflects the fact that this family of ubiquitin adaptor proteins normally helps maintain protein homeostasis in neurons. Their function in health and disease, however, remains poorly understood. In three aims, our investigative team will employ complementary approaches (biochemistry, animal models, and automated microscopy) in an effort to define how UBQLN2 causes FTD/ALS. Our two primary goals are to define pathogenic mechanisms in UBQLN2-mediated FTD/ALS and to gain insight into the cellular pathways driving TDP43 deposition in FTD/ALS. Toward these goals, three aims will seek to define the molecular properties driving aggregation of mutant UBQLN2, explore the functional consequences of UBQLN2 aggregation in mouse models, and investigate how mutant UBQLN2 alters TDP43 homeostasis in neurons. The proposed studies build 1) on novel biochemical insights into the distinct properties of wild type and mutant UBQLN2, 2) newly generated mouse models expressing wild type or mutant UBQLN2 that show robust aggregate pathology selectively in mutant UBQLN2 mice, 3) a completed proteomics screen for interacting proteins that shows wild-type UBQLN2 interacts with other brain-expressed ubiquilins, UBQLN1 and UBQLN4; and 4) evidence that TDP43-positive cytoplasmic puncta accumulate in neurons of mutant UBQLN2 mice, offering a pathway to explore functional links between UBQLN2 and TDP43. The proposed multi-system approach greatly increases the probability of uncovering disease mechanisms that allow us to achieve our overall, long-term objective of finding routes to therapy for FTD/ALS and related neurodegenerative diseases.