At least two mutated RNA-binding proteins, TDP-43 and FUS, have been shown to cause the devastating neurological disease ALS (amyotrophic lateral sclerosis), more commonly known as Lou Gehrig's disease. But those are only two proteins within about 250 others -- some of which, when mutated or misfolded -- may also be implicated in ALS and other neurodegenerative conditions. 

The lab of James Shorter, PhD, associate professor of Biochemistry and Biophysics, set out to isolate new culprits by focusing on RNA-binding proteins that harbor particular prion-like domains (PrLDs). These PrLDs normally help to assemble specific RNA complexes, but their mutated forms contribute to misfolded proteins, which tend to assemble into fibrils that disrupt RNA metabolism, perpetuating the neurological abnormalities that are at the root of ALS and other neurodegenerative disorders. 

A recent study from the Shorter group identified a link between PrLD mutations in the proteins hnRNPA2B1 and hnRNPA1 with ALS. They found these mutations present in two families with a rare inherited form of muscle, bone, and neurologic degeneration, and in another with familial ALS. 

The findings show that the diseases may be initiated either by environmental stress on the PrLDs or by mutations, but the presence of the PrLDs in RNA-binding proteins appears to mark them as definite candidates for causing ALS and other neurodegenerative conditions.  

Next, Shorter says, "We aim to understand how the prion-like domain enables misfolding and whether these RNA-binding proteins access prion-like molecules. We are also elucidating methods to prevent or reverse the misfolding of various RNA-binding proteins with prion-like domains and mitigate their toxicity."

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