One of the hallmarks of neurodegenerative diseases is the abnormal accumulation of protein aggregates due to decreased stability of these disease-associated proteins. This is most likely the case for mutant superoxide dismutase (SOD1) found in familial ALS patients (see January 2011 story). A new study published on February 6 in the Proceedings of the National Academy of Sciences from Samar Hasnain’s group at the University of Liverpool, UK, show that the opposite may be true for TAR DNA binding protein-43 (TDP-43). High cytoplasmic levels of TDP-43 protein are found in the vast majority of sporadic ALS patients, and mutations in the protein are associated with a subset of familial ALS cases. The researchers show that two forms of mutant TDP-43 protein with mutations in the nucleic acid binding domain exhibit increased half-life and thermal stability, as well as resistance to unfolding, rendering them more resistant to degradation and prone to accumulation in the cell. Interestingly, these mutations have little impact on TDP-43 protein secondary, tertiary, or quaternary structure. These new findings reveal a potential new target for drugs that aim to destabilize TDP-43. Click here to read more.
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