Mutations in the cytoplasmic metalloenzyme Cu/Zn superoxide dismutase (SOD1) proteins cause about 20% of familial Amyotrophic Lateral Sclerosis (ALS), and aggresome-like structures formed by mutant SOD1 are associated with the disease. By screening 20,000 compounds for small molecules that inhibit aggresomes, researchers have now found that histone deacetylase (HDAC) inhibitors, and a folate analog, can play a role in preventing protein aggregates from forming larger aggresomes, the cytoplasmic protein inclusion bodies formed by misfolded proteins.
Protein inclusions are associated with a number of neurodegenerative diseases including ALS. In ALS animal models, mutant SOD1 forms aggresome-like structures in motor neurons and astrocytes. It was hypothesized that these aggresomes are the cause of toxicity generated by mutant SOD, but owing to a lack of proper molecular tools it has been difficult to test this hypothesis. In the work reported this week, Dr. Qing Liu and colleagues at Institute of Chemistry and Cell Biology at Harvard Medical School found that HDAC inhibitors and another small molecule, DPDTB, inhibit aggresomes formed by mutant SOD protein labeled with the fluorescent protein tag GFP. The authors believe that the inhibitors act by interfering with the interaction between the misfolded SOD protein and specialized proteins in the cell that transport cargo, the dynein/dynactin transport machinery. The authors note that a recent study by Kawaguchi et al. showing that HDAC6 is directly involved in aggresome formation is consistent with this new finding. Based on the observations now being reported, the authors predict that treating ALS transgenic mice (an animal model for human ALS) with the newly identified inhibitory compounds might alleviate their ALS symptoms and prolong their life span.
Lisa J. Corcoran, Timothy J. Mitchison, and Qing Liu: "A Novel Action of Histone Deacetylase Inhibitors in a Protein Aggresome Disease Model"
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Published in Current Biology, Volume 14, Number 6, 23 March 2003.