A novel mutation in the cleavage site N291 of TDP-43 protein in a familial case of amyotrophic lateral sclerosis

Abstract

Cytoplasmic aggregation of TAR-DNA binding protein (TDP-43) in Amyotrophic Lateral Sclerosis (ALS) and fronto-temporal lobar dementia (FTLD) is associated with post-translational modifications (PTM) and delocalization. Studies on postmortem brains of ALS and FTLD patients showed the existence of TDP-43 fragments that end at position N291. We report a new heterozygous mutation p.N291H in a familial case of ALS. Expression of the mutant protein in cell lines and primary motor neurons induces aggregate formation in the cytoplasm and reduces cell viability. The discovery of mutations at cleavage sites in TDP-43 in patients, which we reviewed here, is valuable for understanding the true role of the various TDP-43 fragments identified in patients and thus, for developing effective targeted therapies for ALS and FTLD treatment.

Keywords:

• ALS
• TARDBP
• fragments

Acknowledgements

The authors thank Dr. D. Lanznaster for reading this article.

Declaration of interest

We have no conflicts of interest to disclose.

Additional information

Funding

This work was supported by the Program ARD2020 (Région Centre Val-de-Loire, France) and INSERM.