Pathological TDP-43 filaments accumulate at synapses and cause synaptic dysfunction.

Area of Science:

• Neuroscience
• Molecular Biology
• Pathology

Background:

• TDP-43 aggregation into amyloid filaments is a key feature of neurodegenerative diseases such as motor neuron disease (MND) and frontotemporal dementia (FTD).
• Synaptic dysfunction and neuronal hyperexcitability are early pathological events in these TDP-43 proteinopathies.
• While mutations in the TARDBP gene confirm TDP-43's role, the mechanisms of filament accumulation and their contribution to neurodegeneration remain unclear.

Purpose of the Study:

• To investigate the early stages of TDP-43 filament accumulation in neurons.
• To identify the molecular interactions and cellular locations of TDP-43 filaments.
• To understand how TDP-43 filament accumulation impacts synaptic function and neuronal excitability.

Main Methods:

• Internalization of patient-derived TDP-43 filaments by mouse and human cortical neurons.
• Proximity labeling to identify TDP-43 filament interactions.
• Electron cryo-tomography (cryo-ET) for high-resolution imaging of TDP-43 filaments in situ.
• Functional measurements of synaptic activity and neuronal excitability.

Main Results:

• TDP-43 filaments were found to accumulate at synapses, specifically near the presynaptic active zone, a finding validated in FTD patient brains.
• Direct visualization via cryo-ET revealed TDP-43 filaments within the presynaptic cytoplasm, interacting with synaptic vesicles and the plasma membrane.
• Accumulation of TDP-43 filaments resulted in presynaptic dysfunction and subsequent neuronal hyperexcitability.

Conclusions:

• Synapses serve as a primary early site for TDP-43 filament accumulation and propagation.
• The study establishes a direct link between TDP-43 filament gain-of-function and synaptic dysfunction.
• These findings highlight the critical role of synaptic pathology in TDP-43 proteinopathies.