TDP-43 Aggregate Seeding Impairs Autoregulation and Causes TDP-43 Dysfunction.

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• TDP-43 protein aggregation, mislocalization, and dysfunction are key features of neurodegenerative diseases.
• Understanding the interplay between TDP-43 aggregation and its functional consequences is crucial for disease mechanism elucidation.

Purpose of the Study:

• To investigate the link between TDP-43 aggregation, cellular mislocalization, and loss of function.
• To explore the role of TDP-43 autoregulation in the context of aggregation-induced pathology.
• To identify factors that modulate TDP-43 aggregation and associated cellular dysfunction.

Main Methods:

• Inducing TDP-43 aggregation using prion-like seeding in cellular models.
• Assessing TDP-43 nuclear localization, function, and target gene expression.
• Analyzing the activation of TDP-43-controlled cryptic exons.
• Investigating the impact of seeding on TDP-43 autoregulation.
• Examining the colocalization of interacting proteins and pathology-associated factors, such as Ataxin 2.

Main Results:

• Prion-like seeding of TDP-43 leads to its gradual loss of nuclear localization and function.
• Aggregate-affected cells exhibit DNA damage and altered expression of TDP-43 targets.
• Proteopathic seeds induce TDP-43-controlled cryptic exon activation in cells, including human neurons.
• TDP-43 autoregulation is impaired by aggregate seeding, disrupting TDP-43 homeostasis.
• Ataxin 2 colocalizes with TDP-43 inclusions and influences seeding-induced aggregation, while normal TDP-43 interactors do not.

Conclusions:

• TDP-43 aggregation, mislocalization, and loss of function are interconnected pathological events.
• Disruption of TDP-43 autoregulation creates a toxic feed-forward loop that exacerbates aggregation.
• This autoregulation disruption may be a central mechanism linking TDP-43 aggregation to its pathological consequences in neurodegeneration.