FTD Basic Mechanisms: Determine role of tau and multiple pathologies

Summary of Key Accomplishments

To advance knowledge about the diverse mechanisms underlying neurodegeneration in FTD, NINDS and NIA funded the team-based “Center without Walls for Mechanisms of Neurodegeneration in Frontotemporal Dementia (FTD)” program. These projects are developing new approaches to better understand several different cellular defects have been associated with FTD. Recently, researchers found that certain mutations in α-synuclein, TDP-43 and tau are not cleared from cells efficiently, leading to certain forms of these proteins being present within cells at higher concentrations and for longer periods of time. Dysregulation of cellular clearance processes may be a common mechanism and potential therapeutic target for FTD and other neurodegenerative diseases.

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. NINDS recently published a funding opportunity to support further development of ADRD human cellular models to recapitulate complex aspects of human disease mechanisms that cause predisposition or resilience to developing ADRD, including FTD.

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. One of the functions of TDP-43 in healthy cells is to regulate how RNA—and ultimately, proteins—is processed in the cell nucleus. Recently, NIH-funded researchers found that in FTD/ALS, TDP-43 leaks from the nucleus and forms clumps in the surrounding cytoplasm. This can lead to cells failing to produce intended proteins and instead generating entirely new proteins. Discovery of these new proteins may enable early diagnosis by serving as biomarkers for monitoring disease progression and therapeutic response in FTD/ALS clinical trials.

Further, mutations in the progranulin 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. NIH- supported researchers have discovered that progranulin mutations in astrocytes (a non-neuronal brain cell thought to support neurons by playing key roles in brain development, function, and homeostasis) can lead to degeneration of synapses, which help facilitate communication between brain cells. In fact, researchers have found that progranulin mutations led to several cell changes within astrocytes and may contribute to astrocyte/glial and neuronal pathology. These discoveries are critical steps toward devising new therapeutic strategies for FTD and FTD-ALS.

The key accomplishments summary is current as of June 2024.