Treatments that maintain the health of synapses may help prevent, mitigate the symptoms of prion disease

Genetic prion disease generally manifests with cognitive difficulties, poor muscle control and abrupt jerking movements of muscle groups and/or entire limbs. The three major phenotypes of genetic prion disease are genetic Creutzfeldt-Jakob disease (gCJD), fatal familial insomnia (FFI), and Gerstmann-Sträussler-Scheinker (GSS) syndrome. The most common cause of inherited prion diseases is the E200K mutation of the prion protein (PrP). It is often thought that this mutation causes disease by making PrP more susceptible to misfolding into a pathogenic shape (PrP^Sc).

However, new research from Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center (BMC) has found that the architecture of neuron-to-neuron contact sites, known as synapses, is altered in neurons expressing this mutant PrP in the absence of PrP^Sc. This suggests that a loss or change in PrP function may contribute to the disease phenotype.

The study is published in the journal Stem Cell Reports.

“Our findings suggest that there could be detectable abnormalities in neurons long before the primary symptoms of inherited prion diseases appear,” explained co-corresponding author David A. Harris, MD, Ph.D., the Edgar Minas Housepian professor and chair of the department of biochemistry & cell biology at the school.

Harris and his colleagues made a large library of induced pluripotent stem cells (iPSCs) (blood cells that have been reprogrammed back into an embryonic-like pluripotent state that enables the development of an unlimited source of any type of human cell needed for therapeutic purposes) from a family harboring this mutation, and differentiated them into neurons.

They then compared the neurons from mutation carriers to neurons from non-carriers. They also used CRISPR/Cas9 technology to correct the mutation in two lines, so they could perform these comparisons between neurons with identical genetic backgrounds aside from the mutation of interest.

According to the researchers, the use of iPSC technology is a step closer to personalized medicine. “Our study employs the largest collection of iPSCs from a family harboring an inherited prion disease that we are aware of. iPSC-derived neurons can provide important mechanistic insights into the pathogenesis of genetic prion diseases, and can offer a powerful platform for testing candidate therapeutics,” said co-corresponding author Gustavo Mostoslavsky, MD, Ph.D., professor of medicine & microbiology at the school and co-director at the BU and BMC Center for Regenerative Medicine.

The researchers believe this study advances understanding of this rare but devastating group of neurodegenerative disorders that damage the connections between nerve cells in the brain, and provides a guide to treatments that may be most effective in combating the symptoms of these disorders.

“Similar therapeutic approaches may also be applicable to Alzheimer’s and other neurodegenerative diseases, some cases of which are inherited,” said Harris.