The role of a metazoan-specific PQC system in protecting against TDP-43 proteinopathies

The overall goal of this application is to elucidate the role of TRIM10 in maintaining solubility and function of TDP-43 and protecting against TDP-43 proteinopathies. TDP-43 is an RNA-binding protein that resides predominantly in the nucleus of healthy cells, regulating various aspects of RNA metabolism. In 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 often misfolds and aggregates in the cytoplasm of affected neurons and glia, which is accompanied by its depletion in the nucleus. Moreover, mutations in TDP-43, which increase its propensity to misfold and aggregate, are associated with a familial subset of ALS and FTD. In both sporadic and familial TDP- 43 proteinopathies, aggregation of TDP-43 largely occurs in an age-dependent manner, suggesting a diminished capacity of a cellular factor(s) that can suppress TDP-43 aggregation early in life. However, the identity and nature of such a factor(s) remains unknown. This conspicuous gap in our knowledge impedes the development of effective therapies. To maintain their proteins in the 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 suggested that animal cells may have a unique and highly potent PQC system consisting of tripartite motif (TRIM) proteins. We found 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 is highly effective in preventing tau aggregation. Our preliminary data further showed that another TRIM (TRIM10) may potently suppress TDP-43 misfolding and aggregation, and its expression may be markedly downregulated in TDP-43 proteinopathies. Here, we propose to test the central hypothesis that TRIM10 is critical for maintaining TDP-43 in its functional soluble state, and downregulation of TRIM10 contributes to the pathogenesis of TDP- 43 proteinopathies. We will (1) characterize the degradative, chaperone, and disaggregase activities of TRIM10 towards TDP-43, (2) determine the effect of TRIM10 on phase behavior and function of TDP-43, and (3) define the role of TRIM10 in the pathogenesis of TDP-43 proteinopathies and explore its utility in disease treatment. Collectively, these studies will enrich our understanding of protein homeostasis and TDP-43 proteinopathies and inform the development of effective therapies.