“We cannot cure patients with polyglutamine diseases. Instead, we have had to resort to symptomatic therapy as the only medical option,” says corresponding author of the study Yoshitaka Nagai. “The goal of our study was to find a new disease-modifying drug for polyglutamine diseases.”
To achieve their goal, the researchers turned to chemical chaperones, molecules that facilitate proper protein folding, to prevent the build-up of protein aggregates. By screening a number of chemical chaperones for their ability to prevent protein aggregation in a test tube, they discovered that arginine, a naturally occurring amino acid, had the strongest inhibiting effect on protein aggregation. In a separate set of experiments using living cells, the researchers then found that arginine was also able to prevent aggregate formation of polyQ proteins.
“These findings show how arginine could alleviate the detrimental effects of polyQ aggregate formation,” says lead author of the study Eiko Minakawa. “We next wanted to know if arginine could slow down or halt the progression of different polyQ diseases in living organisms.”
To test the therapeutic potential of arginine, the researchers utilized well-established mouse models of familial spinocerebellar ataxia, and spinal and bulbar muscular atrophy. When added to their drinking water before symptom onset, arginine inhibited polyQ protein aggregation as well as suppressed motor impairment and neurodegeneration of the mice. Intriguingly, even after the onset of neurological symptoms, arginine was able to ameliorate the detrimental effects of familial spinocerebellar ataxia.
“These are striking results that show how arginine has therapeutic potential for familial spinocerebellar ataxia, which to date has been an incurable disease,” says Nagai. “Our next goal is to conduct clinical trials to use arginine as a novel therapy for polyglutamine diseases including spinocerebellar ataxias.”
