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FTD Basic Mechanisms: Determine role of tau and multiple pathologies (Milestone 2.N)

In Progress

Timeline Start - End

2016 - 2023

Research Implementation Area

Research on Disease Mechanisms

AD-Related Dementias Focus

Clarify unique and converging cellular mechanisms related to tau pathogenesis, C9orf72 hexanucleotide repeat expansions, GRN mutations, and other targets and pathways contributing to FTD neurodegeneration. 

Success Criteria

  • At least one study focused on prion-like mechanisms of tau-driven neurotoxicity. 

  • At least one study to identify mechanisms of C9orf72 pathogenesis in FTD. 

  • At least one study on the role of GRN mutations in FTD pathogenesis. 

Summary of Key Accomplishments

To advance knowledge about the diverse mechanisms underlying neurodegeneration in FTD, NINDS and NIA recently awarded three new grants of the “Center without Walls for Mechanisms of Neurodegeneration in Frontotemporal Dementia (FTD)” program. These team-based science projects are developing new approaches to better understand several different cellular defects have been associated with FTD.

Another NIH-funded project has led to the development of an exciting new non-animal model, called an organoid, which is a 3D multicellular reconstruction of the mouse brain that can better mimic the complex function of a brain than can traditional cellular models. Using these organoids, researchers identified cellular events that precede neurodegeneration in FTD and could potentially be targeted for therapeutic intervention.

NIH-funded researchers have also discovered a mechanistic link between FTD/ALS-linked mutations and abnormal TDP-43 protein aggregation and identified drug candidates that might be able to block this interaction. These mechanistic clues are critically important to develop new therapeutic strategies for FTD.

Further, mutations in the progranulin (PGRN) and C9ORF72 genes are well-established genetic causes of FTD and FTD-ALS, but they seem to trigger different disease pathways that ultimately lead to FTD vs. FTD-ALS. Recently, NIH-funded studies provided new insights into the different ways that PGRN and C9ORF72 mutations cause neurons to die. These discoveries are a critical step toward devising new therapeutic strategies for FTD and FTD-ALS.

The key accomplishments summary is current as of July 2022.  

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