A quantitative cell-based reporter links TDP-43 aggregation and dysfunction to define pathogenic mechanisms.

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• TDP-43 pathology is central to neurodegenerative diseases like ALS and FTD.
• Cytoplasmic TDP-43 aggregates correlate with loss of normal nuclear function.
• Understanding the link between TDP-43 aggregation and dysfunction is crucial.

Purpose of the Study:

• To develop and utilize a cell-based reporter to study TDP-43 aggregation and loss of function.
• To investigate the mechanisms linking TDP-43 aggregation to cellular dysfunction.
• To identify potential therapeutic targets for TDP-43 proteinopathies.

Main Methods:

• Developed a quantitative human biosensor cell line for TDP-43 aggregation and function.
• Used prion-like seeding to induce TDP-43 aggregation.
• Assessed downstream effects including DNA damage and cryptic exon splicing.
• Tested the effect of ataxin-2 reduction on TDP-43 pathology.

Main Results:

• Prion-like seeding of TDP-43 aggregates led to nuclear depletion and loss of function.
• Induced cryptic exon splicing and DNA damage in biosensor cells and human neurons.
• Demonstrated that TDP-43 aggregate seeding disrupts TDP-43 autoregulation and homeostasis.
• Reducing ataxin-2 levels mitigated TDP-43 aggregation and restored function.

Conclusions:

• TDP-43 aggregate seeding initiates a toxic feed-forward mechanism.
• Targeting ataxin-2 offers a strategy to reduce TDP-43 aggregation and toxicity.
• This work provides a platform for studying TDP-43 dysfunction and developing interventions.