James Shorter, associate professor of biochemistry and biophysics at the University of Pennsylvania in Philadelphia, was awarded an MDA research grant totaling $300,000 over a period of three years to develop an experimental approach targeted at protein aggregates in amyotrophic lateral sclerosis (ALS).
In almost all cases of ALS, aggregates or “clumps” of protein accumulate in motor neurons, which may contribute to the death of these cells. Shorter is exploring the possibility that disaggregating [breaking apart] these proteins and returning them to their normal state may be therapeutic. “Unfortunately, mammalian cells have limited ability to disaggregate and renature [properly refold] proteins,” Shorter says, so he employs an enzyme from yeast, called Hsp104.
Shorter is planning to generate variants of the Hsp104 protein that are even more active at breaking up aggregates of the various proteins known to be involved in ALS, including TDP43, FUS and SOD1. After generating such variants, he will test their abilities in yeast and fruit flies, another standard lab model.
“Hsp104-based disaggregases [enzymes that break up aggregates] likely hold great potential as ALS therapeutics,” he says, “as well as for unraveling the role of protein aggregation in ALS pathogenesis.”
Funding for this MDA grant began August 1, 2013.