TDP-43 Regulates Rab4 Levels to Support Synaptic Vesicle Recycling and Neuromuscular Connectivity in Drosophila and...

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Pathological loss of nuclear TDP-43 is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
• TDP-43 dysfunction leads to altered RNA metabolism and neuronal transcript changes.
• The specific effectors linking TDP-43 dysfunction to synaptic defects are not fully understood.

Purpose of the Study:

• To identify key effectors that link TDP-43 dysfunction to synaptic defects.
• To elucidate the regulatory mechanisms underlying synaptic vulnerability in TDP-43 proteinopathies.

Main Methods:

• Utilized *Drosophila* models and human induced pluripotent stem cell (iPSC)-derived motoneurons.
• Investigated the role of Rab4 as a direct target of TDP-43.
• Examined the interaction between Rab4, futsch/MAP1B, and synaptic function.

Main Results:

• Identified Rab4 as a direct and conserved target of TDP-43.
• Demonstrated that Rab4 expression is necessary and sufficient to restore synaptic vesicle recycling, neuromuscular junction growth, and locomotor function in TDP-43-deficient motoneurons.
• Showed that Rab4 activity promotes presynaptic recruitment of futsch/MAP1B, supporting synaptic growth and vesicle turnover.

Conclusions:

• Defined a TDP-43/Rab4/futsch/MAP1B regulatory axis coupling endosomal dynamics to cytoskeletal assembly.
• Provided a mechanistic basis for synaptic vulnerability amplification in TDP-43-related diseases.
• Established a framework for identifying compensatory targets to sustain neuronal function in TDP-43 deficiency.