Disease causing mutants of TDP-43 nucleic acid binding domains are resistant to aggregation and have increased stability and half-life

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Abstract
Significance: Adult onset neurodegenerative diseases are viewed as protein destabilization, misfolding, and aggregation diseases. TAR DNA binding protein-43 (TDP-43) protein is strongly associated with many neurological disorders, particularly amyotrophic lateral sclerosis and frontotemporal lobar degeneration. All of the disease-associated TDP-43 mutants tested have been shown to increase TDP-43 half-life and this correlates inversely with the age at which the sufferer first becomes aware of symptoms. Here we show that disease mutations in two TDP-43 nucleic acid binding domains also increase the protein’s half-life and this is commensurate with increased structural stability and resistance to aggregation. Our results are an unusual contrast to other neurodegenerative diseases and provide a potential link between the molecular characteristics of mutant TDP-43 and the symptoms of these debilitating diseases.

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