Expanding insights into FTD disease mechanisms - PROJECT SUMMARY/ABSTRACT Frontotemporal lobar degeneration (FTLD), which underlies frontotemporal dementia (FTD), encompasses a group of disorders with substantial genetic, clinical, and neuropathological heterogeneity. FTLD is also genetically and pathologically linked to amyotrophic lateral sclerosis (ALS), with some patients developing features of both disorders. Understanding the mechanisms that drive FTLD pathogenesis is a central focus of my research program. We pursue this goal by asking impactful questions and applying innovative approaches to define disease mechanisms and identify opportunities for therapeutic intervention. To accelerate discovery, we have adopted a comprehensive research strategy that investigates multiple FTLD-related mechanisms driven by key molecular players, including C9orf72, TDP-43, progranulin, tau, and, more recently, TMEM106B. We also place strong emphasis on translational research aimed at identifying much-needed biomarkers and therapeutic targets, an area of critical importance given that there are currently no disease-modifying treatments for FTLD. Since the funding of my current R35 at the end of 2016, my group has made seminal discoveries related to FTLD-associated mutations in C9orf72 and GRN and has provided important insight into the consequences of pathogenic TDP-43 and tau deposition in the brain. These findings have led to high-impact publications in Science, Nature, and Cell and have inspired new and ongoing avenues of investigation in my laboratory. The flexibility afforded by the R35 mechanism has also enabled us to expand into related areas of neurodegeneration, including the development of biomarkers and disease models for repeat-associated disorders such as spinocerebellar ataxias. Our productivity is strengthened by the outstanding research environment at the University of Miami, which brings together highly interactive neurobiologists, geneticists, neuropathologists, and physician-scientists. It is further enhanced by the strength of my team, the numerous collaborations we have established with world-renowned experts, and our commitment to stewardship, rigor, resource sharing, and dissemination of knowledge to the scientific community. Building on our prior work in FTLD, we now propose to address several cutting-edge questions: (1) the molecular determinants of TDP-43 localization and function and the downstream consequences of its dysfunction in disease; (2) the mechanisms underlying cryptic splicing in TDP-43 proteinopathies and the roles of cryptic RNAs and proteins in FTLD; (3) the contribution of the endo-lysosomal system to the development of TDP-43 pathology and neurodegeneration; and (4) the emerging role of TMEM106B fibrillogenesis in neurodegenerative diseases, including TDP-43 proteinopathies and tauopathies. We will use induced human pluripotent stem cell models, transcriptomics, proteomics, histology, and human postmortem tissue analyses to carry out these studies and to address new and potentially transformative ideas as they emerge.
