A New Clue in the Mystery of ALS, Frontotemporal Dementia

A study published in Cell Reports localized a structure within the TDP-43 protein that is essential to its ability to induce nerve cell death in persons with amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD), reports Medical Xpress . This finding could help gain insights into designing a means to suppress this function. "By manipulating the structure of the protein, we determined that RNA binding is pivotal for maintaining the stability, function, and toxicity of TDP-43 in disease models," says University of Michigan Professor Sami Barmada. According to his team, too much TDP-43 destabilizes RNA, especially those involved in energy and protein production, and they identified an identical pattern in cells from persons with ALS. Their introduction of specific mutations to TDP-43 interrupted an interaction between two parts of the protein needed for RNA binding, generating non-RNA-binding variants. The team learned when TDP-43 cannot bind RNA it quickly degrades. Additional research demonstrated that modifying TDP-43 structure strips its ability to bind RNA and cause nerve cell death in models of ALS and FTD.