Role of TRIM11 in regulating TDP-43 and FUS - PROJECT SUMMARY/ABSTRACT The overall objective of this application is to determine the role of TRIM11 in regulating transactive response DNA-binding protein 43 (TDP-43) and fused-in-sarcoma (FUS) and protecting against TDP-43/FUS-related proteinopathies. TDP-43 and FUS are prion-like RNA binding proteins (RBPs) with multiple cellular functions. In healthy cells, these proteins reside predominantly in the nucleus. In various progressive and fatal neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), limbic predominant age-related TDP-43 encephalopathy (LATE), and other Alzheimer's disease-related dementia (ADRD), TDP-43 or FUS mis-localizes to the cytoplasm and forms cytotoxic inclusions in affected neurons and glia, which is accompanied by their depletion in the nucleus and loss of their normal functions. What regulates the solubility and function of TDP-43 and FUS is not well understood. This conspicuous gap in our knowledge impedes the development of effective therapies. To maintain proteins in their functional soluble form, organisms in all kingdoms of life rely on protein quality control (PQC) systems. Over the past decade, research in my lab has revealed the existence of a unique and potent PQC system in animal cells, which consists of tripartite motif (TRIM) proteins. We showed that individual TRIM proteins possess multiple activities to enable protein folding, and they operate via a mechanism distinct from canonical, ATP-dependent PQC systems. More recently, we demonstrated that TRIM11 prevents aggregation of a-synuclein and tau. Our preliminary data further suggest that TRIM11 may also suppress TDP-43 and FUS misfolding and aggregation, and its expression may be reduced in TDP-43 proteinopathies. Here, we propose to test the central hypothesis that TRIM11 is critical for keeping TDP-43 and FUS in their functional soluble state, and its downregulation contributes to the pathogenesis of TDP-43/FUS-related proteinopathies. We will (1) determine the role of TRIM11 in regulating solubility and liquid-liquid phase separation of TDP-43 and FUS, (2) elucidate the effect of TRIM11 on the localization and function of TDP-43 and FUS, and (3) define the role of TRIM11 in TDP-43/FUS-related proteinopathies and explore its utility in disease treatment. Collectively, these studies will enrich our understanding of protein homeostasis in animal cells and the pathogenesis of various devastating neurodegenerative diseases. They will also provide valuable information for the development of effective therapies.
