The most prevalent reason for inherited prion diseases is the E200K mutation found in the prion protein (PrP). It is commonly believed that this mutation leads to disease by increasing the likelihood of PrP misfolding into a harmful form (PrPSc). However, recent research reveals that the structure of synapses, the sites where neurons connect with one another, is altered in cells that express this mutated PrP even without the presence of PrPSc. This indicates that changes in the function of PrP might play a role in the onset of the disease.
Inherited prion disease typically presents with cognitive issues, impaired muscle coordination, and sudden involuntary muscle spasms or jerking movements in muscle groups or entire limbs. The primary types of genetic prion disease include genetic Creutzfeldt-Jakob disease (gCJD), fatal familial insomnia (FFI), and Gerstmann-Sträussler-Scheinker (GSS) syndrome. The most widespread cause of these inherited prion diseases is the E200K mutation in the prion protein (PrP). It is often believed that this mutation leads to disease by making PrP more prone to misfolding into a harmful conformation (PrPSc).
New research conducted at the Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center (BMC) has discovered that the architecture of synapses is changed in neurons expressing the mutant PrP, even when PrPSc is not present. This points to the possibility that alterations or loss in PrP function may be involved in the disease’s symptoms.
“Our results indicate that abnormalities in neurons may be detectable well before the main symptoms of inherited prion diseases develop,” remarked co-corresponding author David A. Harris, MD, PhD, the Edgar Minas Housepian professor and chair of the biochemistry & cell biology department at the institution.
Harris and his team created a comprehensive library of induced pluripotent stem cells (iPSCs) from a family with this mutation and converted them into neurons. They compared the neurons from individuals with the mutation to those without it. In two lines, they also used CRISPR/Cas9 technology to rectify the mutation, allowing them to make direct comparisons between neurons with the same genetic make-up apart from the specific mutation.
The researchers assert that utilizing iPSC technology brings them closer to personalized medicine. “Our study features the largest collection of iPSCs from a single family with an inherited prion disease that we are aware of. Neurons derived from iPSCs can shed light on the mechanisms behind genetic prion diseases and provide a valuable platform for evaluating potential treatments,” stated co-corresponding author Gustavo Mostoslavsky, MD, PhD, a professor of medicine and microbiology at the institution and co-director of the BU and BMC Center for Regenerative Medicine.
The findings of this research enhance the understanding of these rare but debilitating neurodegenerative disorders, which disrupt connections between brain cells, and offer guidance on the most effective treatments for alleviating the symptoms. “Similar therapeutic strategies might also be relevant for Alzheimer’s and other inherited neurodegenerative diseases,” Harris noted.
These findings have been published online in Stem Cell Reports.
Nhat T.T. Le was granted support through a Warren Alpert Distinguished Scholar Award (Letter dated 3/28/2019). The Mostoslavsky lab is funded by NIH Grants N0175N92020C00005 and 1R01DA051889-01, along with a grant from the CJD Foundation. The Harris lab received support from NIH R01 NS065244. Additional support for this work came from NIH grant 1R21NS111499-01 for GM and DAH.
