Causes of ALS: TDP-43 Mutation

Recently, a new gene was uncovered as a relatively common cause of familial ALS. Patients with the mutated form of the TDP-43 gene appear to have an abnormal cell protein that unnaturally clumps or aggregates in motor neurons. This parallels what happens in Alzheimer’s and Parkinson’s disease, which also have unnatural aggregates in nervous system cells.

Forming aggregates is an important sign. But what most excites Packard and other scientists is that TDP-43 mutations have been spotted both in familial and in sporadic ALS patients. Granted, they appear less common in the sporadic cases, but that could change with more study.

TDP-43 directs the production of proteins that bind RNA.* Because RNA is a key element in assembling proteins from amino acids and in proteins’ ultimate shaping, scientists suspect that the mutated gene upsets this process – more research will tell.

Packard investigators are especially eager to discover exactly how mutant TDP-43 damages cells, to see if it does, indeed, upset RNA metabolism. That’s because their earlier discovery of ALS excitotoxicity showed that faulty RNA metabolism plays a major part in that greatly destructive process.

Being able to link a mutant gene to one of the most cell-damaging happenings in ALS would be the most important find in ALS pathology research to date.

As it is, TDP-43 has the potential to lead to an entirely different set of scientific observations, not to mention finding biomarkers for ALS, improved imaging of the disease and new animal models. All of that would set us more firmly on a road to therapy.

Learn more about the research projects funded and coordinated by the Packard Center for ALS Research at Johns Hopkins, and targeted at finding the causes of ALS and a cure. Subscribe to ALS Alert to stay informed about ALS research and clinical trials.

*Another newly-discovered gene, called FUS, has also been found in familial ALS patients and also codes for proteins that seem important in RNA processing. FUS, like TDP-43, is found in some sporadic ALS patients.