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A decade ago, scientists identified mutations in TDP-43 as a relatively common genetic cause of ALS.

TDP-43 directs the production of proteins that bind RNA. RNA directs the assembly of proteins from amino acids and helps to shape the final product. Scientists suspect that mutations in TDP-43 somehow upsets this process.

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.

Mutations in the gene coding for TDP-43 also causes clumps or aggregates in motor neurons. Alzheimer’s and Parkinson’s diseases also involve toxic protein 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 identified both in familial and in sporadic ALS patients.

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.

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