FTD Basic Mechanisms: Characterize TDP-43 and FUS roles in FTD

AD-Related Dementias Focus

Determine the mechanism of TDP-43 and FUS pathogenesis and toxicity.

2028 RFA-NS-18-015: Structural Biology of Alzheimer's Disease Related Dementias (ADRDs) Proteinopathies (U01) PAS-19-392: Small Research Grant Program for the Next Generation of Researchers in AD/ADRD: Area of Focus Basic Science (R03) RFA-NS-20-005: Mechanistic Basis of TDP-43-Dependent Pathobiology in Common Dementias (R01) RFA-NS-21-003 –Center without Walls for Mechanisms of Neurodegeneration in Frontotemporal Dementia (FTD) RFA-NS-21-003: Center without Walls for Mechanisms of Neurodegeneration in Frontotemporal Dementia (FTD) (U54 Clinical Trial Not Allowed) RFA-NS-21-006: Mechanisms of Pathological Spread of Abnormal Proteins in LBD and FTD (R01 Clinical Trial Not Allowed) RFA-NS-21-007: Mechanisms of Selective Vulnerability in LBD and FTD (R01 Clinical Trial Not Allowed) PAR-23-211: Mechanistic Investigations into ADRD Multiple Etiology Dementias (R01 - Clinical Trial Not Allowed) PAR-23-212: Investigating Distinct and Overlapping Mechanisms in TDP-43 Proteinopathies, including in LATE, FTD & other ADRDs (R01 - Clinical Trial Not Allowed) 2.P In Progress DN 2016 ADRD Summit: Frontotemporal Lobar Degeneration (FTD) Focus Area 1: Basic Science: Pathogenesis and Toxicity, Recommendation 3 NINDS Press Release: Silencing a faulty gene may uncover clues to rare forms of ALS Workshop: LATE 2022 Press Release: Abnormal proteins found in the spinal fluid of people with ALS and frontotemporal dementia Highlight: Abnormal proteins found in the spinal fluid of people with ALS and frontotemporal dementia Research on Disease Mechanisms ARTFL-LEFFTDS Structural Biology of Alzheimer's Disease Related Dementias (ADRDs) Proteinopathies National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD) NINDS Human Biomarkers Biospecimen and Data Repository (BioSEND) NINDS Human Cell and Data Repository (NHCDR) ALLFTD Keystone Symposium: Neurodegenerative Diseases: New Insights and Therapeutic Opportunities (Z2) Select projects funded in FY21 Select projects funded in FY22

  • Support research to identify the predominant mechanism(s) of TDP-43 and FUS-related pathogenesis and neurodegeneration in FTD.
  • Determine if and how aggregated TDP-43 spreads.

Summary of Key Accomplishments

Abnormal clumps of the proteins TDP-43 and FUS are a hallmark of FTD, ALS and related neurodegenerative diseases. Ongoing NIH-funded projects are providing new insights into how these aggregates form. For example, recent studies have shown that TDP-43 forms droplets inside cells that are prone to turn into a gel or solid during times of cellular stress. Other studies have shown that defects in the cell nucleus lead to TDP-43 and FUS dysfunction, ultimately resulting in neuronal death. Novel possible targets for therapeutic intervention in FTD and FTD-ALS are emerging from this research.

The key accomplishments summary is current as of July 2022.