TDP-43 Aggregate Seeding Impairs Autoregulation and Causes TDP-43 Dysfunction
Mamede, L. D.; Hu, M.; Titus, A. R.; Vaquer-Alicea, J.; French, R. L.; Diamond, M. I.; Miller, T. M.; Ayala, Y. M.
Show abstract
The aggregation, cellular mislocalization and dysfunction of TDP-43 are hallmarks of multiple neurodegenerative disorders. We find that inducing TDP-43 aggregation through prion-like seeding gradually diminishes normal TDP-43 nuclear localization and function. Aggregate-affected cells show signature features of TDP-43 loss of function, such as DNA damage and dysregulated TDP-43-target expression. We also observe strong activation of TDP-43-controlled cryptic exons in cells, including human neurons treated with proteopathic seeds. Furthermore, aggregate seeding impairs TDP-43 autoregulation, an essential mechanism controlling TDP-43 homeostasis. Interestingly, proteins that normally interact with TDP-43 are not recruited to aggregates, while other factors linked to TDP-43 pathology, including Ataxin 2, specifically colocalize to inclusions and modify seeding-induced aggregation. Our findings indicate that TDP-43 aggregation, mislocalization and loss of function are strongly linked and suggest that disruption of TDP-43 autoregulation establishes a toxic feed-forward mechanism that amplifies aggregation and may be central in mediating this pathological connection.
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