These vacuoles appear initially in the deep part of the cortex and then progress to affect almost all parts of the brain. After Gunn, He, and Barsh identified how mahoganoid mutations affected the brains of the mice, they began to search for the malfunctioning gene. The researchers constructed a high-resolution genetic map that aided in narrowing their search to a region of the genome containing about 30 genes. Through additional genetic analyses, the scientists pinpointed the abnormal gene and showed that it appeared to be a member of the machinery in the cell that destroys unwanted proteins.
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The gene, which the researchers named Mahogunin , encodes a protein that attaches molecular tags called ubiquitins to other proteins to mark them for destruction. Further experiments revealed evidence that the Attractin protein—which is a receptor-like protein—might somehow act as a regulator of Mahogunin , both in the pigmentation and neural pathways.
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More broadly, Barsh said, the findings implicate this pathway in spongiform degenerative diseases. The researchers' studies also demonstrate the value of animal models of disease. That is, one can generate mutations and analyze them efficiently much the same way that people do with invertebrate model genetic systems such as flies or worms.
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Possible molecular pathway for neurodegeneration in prion diseases
Prion diseases, of which Creutzfeld-Jakob is the most common, are rare diseases. They are character-ized by dementia in addition to neurological signs vision problems, coordination deficits…. Once the first symptoms have occurred, the evolution is rapid and leads to death within a few months. To this date, no standard treatment has been found.
The prion protein, or PrP is present in most of our cells. While it is strongly conserved across species, its role is still poorly understood. The deposits of proteins multiply and accumulate both inside and outside neu-rons, leading to their dysfunction, and ultimately, degeneration. The propagation of prions relies on their ability to interact with the normal form of the prion protein and to change the conformation of the normal proteins, converting them into pathological forms.
The team is interested in, among other aspects, the molecular mechanisms implicated in the propagations of prions, and more precisely, the phenomenon of converting normal PrP proteins into toxic, malformed PrPsc proteins that accumu-late, propagate, and lead to the death of neurons.
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The reseachers developed amplification methods of malformed proteins in vitro in order to observer the misfolding process incorrect folding of proteins and to understand its role in the mechanisms of neuronal death. These methods allow, on one hand, studying of the propagation mechanisms and to model the barriers to transmission of these agents, and on the other hand, to develop diagnostic ap-proaches with high sensitivity and specificity and to test therapeutic molecules.
Understanding this phenomenon is a major challenge for attempting to block it and to find new treatments adapted to these pathologies. For example, the first cellular system allowing propagation of different human sources of prions was obtained. This is a precious tool for the research of therapeutic molecules.
Neurodegeneration and Prion Disease
In-deed, the action of anti-prion treatment often varies in function of origins of the prions, it is thus criti-cal to evaluate efficiency of treatment with respect to prions isolated directly from affected patients. The proteins that result from the cleavage by TACE are not toxic for the brain and even play a protective role for neurons.
The ab-sence of TACE leads to a faulty physiological cleavage of the non-pathological cellular prion protein PrPc or of the amyloid precursor protein APP that consequences in production of abnormal toxic proteins. The rarity of Creutzfeld-Jakob Disease new cases per million of habitatnts , the distribution, and sub-acute evolution of the disease have for a long time limited the ability to perform controlled clini-cal trials, in which in efficiency of a new therapeutic is compared to a placebo.