Summary: New research has revealed that prion illness mutations does affect neuron synapses’ structure long before symptoms become apparent. Even in the absence of misfolded prion proteins, scientists examined neurons derived from induced pluripotent stem cells (iPSCs ) of patients with the E200K prion protein mutation.
This finding points to the possibility that first brain damage may result from a decline in regular prion function. The study demonstrates how mesenchymal systems can advance our understanding of prion diseases and aid in the development of novel treatments.
Important Facts:
- Before signs develop, neuronal synapses are disrupted by Prion disease mutations.
- Experts are able to analyze the first stages of prion illnesses using cells made of iPSC.
- Results may provide insights that can be applied to different degenerative diseases.
Origin: Boston University
Biological prion illness typically manifests as poor muscle power, sudden jerking of muscles, and/or limb movements.
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 prion protein ( PrP ) E200K mutation is the most prevalent cause of inherited prion diseases. It is frequently believed that this mutation makes PrP more prone to misfolding into a pathogenic shape ( PrPSc ) and causes disease.
In contrast, recent research from Boston University Chobanian &, Avedisian School of Medicine, and Boston Medical Center ( BMC) has discovered that neurons expressing this mutant PrP without PrPSc‘s architecture, known as synapses, are altered in neurons. This suggests that a change or loss in PrP work may be a factor in the condition trait.
Our findings point to the possibility of visible defects in neurons well before the start of inherited prion diseases, according to co-author David A. Harris, MD, PhD, the Edgar Minas Housepian professor and chair of the school’s cell biology office.  ,  ,
A family with this mutation was the subject of a large collection of induced pluripotent stem cells ( blood tissues that have been reprogrammed back to an embryonic-like pluripotent state that allows the development of an endless source of any type of human body needed for therapeutic purposes ) from a family that harbored this gene. Harris and his associates divided these cells into neurons. Finally, they compared the cells from carriers of mutations to those from non-carriers.
In order to conduct these similarities between neurons with the same genetic background but different mutations, they even used CRISPR/Cas9 engineering to correct the gene in two lines.
According to the experts, the use of mesenchymal technology is a move closer to personal medicine.
The largest selection of iPSCs from a home with an inherited prion condition that we are aware of is used for our review. iPSC-derived neurons may provide significant mechanistic insights into the pathogenesis of biological prion diseases, and may offer a strong platform for testing candidate therapeutics”, said co-corresponding author Gustavo Mostoslavsky, MD, PhD, professor of medicine &, microbiology at the school and co-director at the Post and BMC Center for Regenerative Medicine.
The experts believe that this research advances our understanding of this uncommon but destructive group of neurological disorders, which harm the relationships between brain nerve cells, and provides a guide to the treatments that may be most effective in addressing 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.
These findings appear online in , Stem Cell Reports.
Funding: Nhat T. T. Le was supported by a Warren Alpert Distinguished Scholar Award ( Ltr dtd 3/28/2019 ). Work in the Mostoslavsky lab is supported by NIH Grants N0175N92020C00005 and 1R01DA051889-01 as well as a grant from the CJD Foundation. Work in the Harris lab is supported by NIH R01 NS065244. This work was also supported by NIH grant 1R21NS111499-01 to GM and DAH.
About this news about genetics research and prion disease
Author: Gina DiGravio
Source: Boston University
Contact: Gina DiGravio – Boston University
Image: The image is credited to Neuroscience News
Original Research: Open access.
” Abnormal synaptic architecture in iPSC-derived neurons from a multi-generational family with genetic Creutzfeldt-Jakob disease” by David A. Harris et al. Stem Cell Reports
Abstract
Abnormal synaptic architecture in iPSC-derived neurons from a multi-generational family with genetic Creutzfeldt-Jakob disease
Genetic prion diseases are caused by mutations in , PRNP, which encodes the prion protein ( PrPC ). Why these mutations are pathogenic, and how they alter the properties of PrPC , are poorly understood.
We have consented and accessed 22 individuals of a multi-generational Israeli family harboring the highly penetrant E200K , PRNP , mutation and generated a library of induced pluripotent stem cells (iPSCs ) representing nine carriers and four non-carriers.
A misalignment of postsynaptic NMDA receptors with the cytoplasmic scaffolding protein PSD95 causes abnormal synaptic architecture in iPSC-derived neurons from E200K carriers.
The absence of a physiological function of PrPC  may contribute to the disease phenotype because differentially differentiated neurons from mutation carriers do not produce PrPSc, the aggregated and infectious conformer of PrP.
Our study demonstrates that the use of iPSC-derived neurons can provide important mechanistic insights into the pathogenesis of genetic prion diseases as well as provide a potent platform for the evaluation of potential therapeutics.
