Researchers at the University of Massachusetts Amherst have discovered that a mutation in the misfolding protein that causes Parkinson’s disease offers protection against the fatal neurodegenerative disorder multiple system atrophy (MSA). The discovery may lead to a more personalized approach for MSA.

The findings are published in PLoS Pathogens in an article titled, “The E46K mutation modulates α-synuclein prion replication in transgenic mice,” and led by Amanda Woerman, PhD, assistant professor of biology in the UMass Amherst College of Natural Sciences.

MSA is a rare neurodegenerative disorder that can cause a multitude of symptoms in any combination including impairments to balance, difficulty with movement, poor coordination, bladder dysfunction, sleep disturbances, and poor blood pressure control. The disease was first known as Shy-Drager Syndrome. Currently, it is believed that MSA is “sporadic,” meaning that there are no established genetic or environmental factors that cause the disease.

Amanda Woerman, PhD, is an assistant professor of biology at UMass Amherst. [UMass Amherst]
“In MSA, the α-synuclein protein misfolds into a self-templating prion conformation that spreads throughout the brain, leading to progressive neurodegeneration,” wrote the researchers. “While the E46K mutation in α-synuclein causes familial Parkinson’s disease (PD), we previously discovered that this mutation blocks in vitro propagation of MSA prions. Recent studies by others indicate that α-synuclein adopts a misfolded conformation in MSA in which a Greek key motif is stabilized by an intramolecular salt bridge between residues E46 and K80.”

“This lays the groundwork for our gene therapy strategy,” explained Woerman. “Our results tell us that a single change in the genome can have a protective effect against MSA.”

The Woerman Lab is focused on studying the misfolding and aggregation of alpha-synuclein (a-synuclein) and several other proteins.

“A really big question in my lab is: how does a single protein misfolding cause a variety of diseases? What’s that mechanism that allows the protein α-synuclein to cause both MSA, as well as Parkinson’s disease?”

“We have the substrate that we know makes Parkinson’s, but which variations of these substrates can also form MSA? We ended up finding that this α-synuclein mutation, E46K, is not able to fold into the MSA shape, so it essentially blocks disease progression. That experiment was exciting in terms of understanding more about the strain hypothesis, and how particular differences in individual genomes can drive or determine disease susceptibility,” Woerman said.

Mice expressing E46K alpha-synuclein developed neuropathological inclusions in the brain (shown in green) following injection with recombinant E46K fibrils. Red staining shows astrocytes, blue is cell nuclei. [Woerman Lab, UMass Amherst]
The researchers observed that the E46K mutation similarly blocks MSA transmission in mice over a 475-day incubation period.

“This tells us that a single change in the genome can have a protective effect against MSA,” Woerman said. “The downside is it’s a mutation that we know causes Parkinson’s disease.”

“My lab is continuing to tap into this discovery that there are single changes that we can make in the protein sequence to exert a protective effect against neurodegenerative disorders,” Woerman said, adding that this research would not be possible without the donations to brain banks by families who lost loved ones to these diseases.

“We think a lot about the lost lives that enable us to make these discoveries,” she said. “If what we are doing leads to a treatment—and maybe even a cure—what greater way is there to honor that gift?”