TDP–43, Protein Aggregation, and Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disorder and the third most common neurodegenerative cause of adult death after Alzheimer’s and Parkinson’s diseases. TAR DNA binding protein (TDP-43) has been found to be a major component of inclusion bodies in motor neurons of ALS patients. Inclusion bodies are protein aggregates considered a pathological hallmark of neurodegeneration. Our group and eight independent research groups screened TDP-43 for mutations. Overall, 19 missense mutations and one truncating mutation were identified only in ALS patients. These mutations were not found in a considerable number of controls sequenced in several independent studies. Ten of these mutations were found in patients with a family history of ALS. To further support a pathogenic role, the mutations segregated with the disease in three families, including one family with a significant logarithm of odds (LOD) score. Nineteen of these 20 mutations are located in the C-terminus of the TDP-43 protein. These mutations could disrupt several of the already known functions of TDP-43, including nuclear localization, exon splicing, and RNA and heterogenous ribonucleoprotein particle (hnRNP) binding, or could introduce a novel gain of function that is toxic to motor neurons. In the future, animal and cellular models using these mutations should elucidate the role of TDP-43 mutations in ALS pathogenesis and could provide new means to test pharmaceutical compounds for this neurological disease.