Thursday, April 3, 2025
4/3/2025
Expanding insights into FTD disease mechanisms - PROJECT SUMMARY/ABSTRACT Frontotemporal lobar degeneration (FTLD), which underlies frontotemporal dementia (FTD), encompasses a group of disorders with significant genetic, clinical, and neuropathological heterogeneity. FTLD is also genetically and pathologically associated with the motor neuron disease amyotrophic lateral sclerosis (ALS), with some patients developing both disorders. Understanding the diverse mechanisms governing FTLD pathogenesis is a fundamental area of interest of my research program, and we pursue this goal by asking impactful questions and applying innovative techniques. To accelerate scientific discovery, we have adopted a comprehensive approach that investigates multiple FTLD mechanisms driven by key molecular players like C9orf72, TDP-43, progranulin, tau and, more recently, TMEM106B. We also place great emphasis on translational research geared towards identifying much needed biomarkers and therapies, an area of particular importance given that there exists no treatment for FTLD. Since the funding of my current R35 at the end of 2016, my group has uncovered seminal findings related to the pathomechanisms mediated by FTLD-associated mutations in C9orf72 and GRN and shed crucial insight into the consequences of pathogenic TDP-43 and tau deposition in the brain. These findings have garnered high-impact publications in Science, Nature, and Cell and inspired new and ongoing avenues of research in my lab. The flexibility afforded by the R35 funding opportunity also allowed us to branch into other related topics and tackle urgent issues in the broader neuroscience field, including the need for biomarkers and mouse models for distinct repeat-associated disorders like spinocerebellar ataxias and the recent pressing need for tools to study and understand COVID-19 and its impact on the brain. Our productivity is influenced by the excellent research environment fostered at Mayo Clinic, which brings together highly interactive and devoted neurobiologists, geneticists, neuropathologists and physician scientists, the diversity of my team, and the numerous collaborations we have forged with world-renowned experts in the field, as well as our dedication to stewardship and the sharing of information and resources with the scientific community at large. Drawing from our past work on FTLD, we now propose to explore current cutting-edge questions related to: (1) the molecular underpinnings 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 role of cryptic RNA and proteins in FTLD, (3) the role of the endo-lysosomal system in the development of TDP-43 pathology and neurodegeneration, and (4) the emerging role of TMEM106B fibrillogenesis in diverse neurodegenerative diseases including TDP-43 proteinopathies and tauopathies. We will use a combination of mouse and induced pluripotent stem-cell modeling, transcriptomics, proteomics, histology, and human tissue analyses to carry-out our proposed studies and address new and potentially transformative ideas as they emerge.
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