Monomerization of TDP-43 is a key determinant for inducing TDP-43 pathology in amyotrophic lateral sclerosis

Researchers at Nagoya University and Aichi Medical University found that TDP-43 dimerization/multimerization is impaired in the postmortem brains and spinal cords of patients with sporadic amyotrophic lateral sclerosis (ALS). Expression of N-terminal dimerization-deficient mutant TDP-43 in Neuro2a cells and induced pluripotent stem cell-derived motor neurons recapitulates TDP-43 pathology. Moreover, TDP-DiLuc, a novel reporter assay to evaluate TDP-43 dimerization/multimerization, could detect decreased N-terminal dimerization of TDP-43 prior to the TDP-43 pathological changes. Our findings may be important in future research on early pathogenic events related to TDP-43 and in the search for early diagnostic markers or therapeutic strategies for ALS.
This work was published in the journal Science Advances on August 4, 2023.

Key Points
• TDP-43 dimerization/multimerization is impaired in the postmortem brains and spinal cords of patients with sporadic amyotrophic lateral sclerosis (ALS).
• Expression of N-terminal dimerization-deficient mutant TDP-43 in Neuro2a cells and induced pluripotent stem cell-derived motor neurons recapitulates TDP-43 pathology.
• TDP-DiLuc, a novel reporter assay to evaluate TDP-43 dimerization/multimerization, could detect decreased N-terminal dimerization of TDP-43 prior to the TDP-43 pathological changes.
• Our findings may be important in future research on early pathogenic events related to TDP-43 and in the search for early diagnostic markers or therapeutic strategies for ALS.

Publication