Major prion protein: Difference between revisions

▲*[[Creutzfeldt–Jakob disease]] – [[glutamic acid]]-200 is replaced by [[lysine]] while [[valine]] is present at amino acid 129

▲In addition, some prion diseases can be transmitted from external sources of PrP^Sc.<ref name = "pmid19308092">{{cite journal | vauthors = Hwang D, Lee IY, Yoo H, Gehlenborg N, Cho JH, Petritis B, Baxter D, Pitstick R, Young R, Spicer D, Price ND, Hohmann JG, Dearmond SJ, Carlson GA, Hood LE | title = A systems approach to prion disease | journal = Mol. Syst. Biol. | volume = 5 | issue = 1 | pages = 252 | year = 2009 | pmid = 19308092 | pmc = 2671916 | doi = 10.1038/msb.2009.10}}</ref>

▲*[[Scrapie]] – fatal neurodegenerative disease in sheep, not transmissible to humans

▲*[[Bovine spongiform encephalopathy]] (mad-cow disease) – fatal neurodegenerative disease in cows, which can be transmitted to humans by ingestion of brain, spinal, or digestive tract tissue of an infected cow

▲*[[Kuru (disease)|Kuru]] – TSE in humans, transmitted via funerary cannibalism. Generally, affected family members were given, by tradition, parts of the central nervous system according to ritual when consuming deceased family members.

▲=== Alzheimer's disease ===

▲PrP^C protein is one of several cellular receptors of soluble [[amyloid beta]] (Aβ) oligomers, which are canonically implicated in causing [[Alzheimer's disease]].<ref name= "Laurén_2014" >{{cite journal | vauthors = Laurén J | title = Cellular prion protein as a therapeutic target in Alzheimer's disease | journal = Journal of Alzheimer's Disease | volume = 38 | issue = 2 | pages = 227–244 | date = 2014 | pmid = 23948943 | doi = 10.3233/JAD-130950 }}</ref> These [[oligomer]]s are composed smaller Aβ plaques, and are the most damaging to the integrity of a [[neuron]].<ref name="Laurén_2014" /> The precise mechanism of soluble Aβ oligomers directly inducing [[neurotoxicity]] is unknown, and experimental deletion of ''PRNP'' in animals has yielded several conflicting findings. When Aβ oligomers were injected into the [[Ventricular system|cerebral ventricles]] of a mouse model of Alzheimer's, ''PRNP'' deletion did not offer protection, only anti-PrP^C antibodies prevented long-term memory and [[spatial learning]] deficits.<ref name= "Zhou_2013" >{{cite journal | vauthors = Zhou J, Liu B | title = Alzheimer's disease and prion protein | journal = Intractable & Rare Diseases Research | volume = 2 | issue = 2 | pages = 35–44 | date = May 2013 | pmid = 25343100 | doi = 10.5582/irdr.2013.v2.2.35 | pmc=4204584}}</ref><ref name= "Laurén_2009" >{{cite journal | vauthors = Laurén J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM | title = Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers | journal = Nature | volume = 457 | issue = 7233 | pages = 1128–1132 | date = Feb 2009 | pmid = 19242475 | doi = 10.1038/nature07761 | pmc=2748841 | bibcode = 2009Natur.457.1128L}}</ref> This would suggest either an unequal relation between PRNP and Aβ oligomer-mediated [[neurodegeneration]] or a site-specific relational significance. In the case of direct injection of Aβ oligomers into the [[hippocampus]], ''PRNP''-knockout mice were found to be indistinguishable from control with respect to both neuronal death rates and measurements of [[synaptic plasticity]].<ref name="Laurén_2014" /><ref name="Laurén_2009" /> It was further found that Aβ-oligomers bind to PrP^C at the [[postsynaptic density]], indirectly overactivating the [[NMDA receptor]] via the [[FYN|Fyn]] enzyme, resulting in [[excitotoxicity]].<ref name="Zhou_2013" /> Soluble Aβ oligomers also bind to PrP^C at the [[dendritic spines]], forming a complex with Fyn and excessively activating [[Tau protein|tau]], another protein implicated in Alzheimer's.<ref name="Zhou_2013" /> As the gene [[FYN]] codes for the enzyme Fyn, FYN-knockout mice display neither [[excitotoxic]] events nor [[dendritic spine |dendritic spine shrinkage]] when injected with Aβ oligomers.<ref name="Zhou_2013" /> In mammals, the full functional significance of PRNP remains unclear, as ''PRNP'' deletion has been prophylactically implemented by the cattle industry without apparent harm.<ref name="Laurén_2014" /> In mice, this same deletion [[phenotypically]] varies between Alzheimer’s mouse lines, as hAPPJ20 mice and TgCRND8 mice show a slight increase in [[epileptic]] activity, contributing to conflicting results when examining Alzheimer's survival rates.<ref name="Laurén_2014" /> Of note, the deletion of ''PRNP'' in both APPswe and SEN1dE9, two other [[transgenic]] models of Alzheimer’s, attenuated the epilepsy-induced death phenotype seen in a subset of these animals.<ref name="Laurén_2014" /> Taken collectively, recent evidence suggests PRNP may be important for conducing the neurotoxic effects of soluble Aβ-oligomers and the emergent disease state of Alzheimer's.<ref name="Laurén_2014" /><ref name="Zhou_2013" /><ref name="Laurén_2009" />

▲In humans, the [[methionine]]/[[valine]] [[Genetic polymorphism|polymorphism]] at [[codon]] 129 of ''PRNP'' (rs1799990) is most closely associated with Alzheimer's disease.<ref name="He_2013">{{cite journal | vauthors = He J, Li X, Yang J, Huang J, Fu X, Zhang Y, Fan H | title = The association between the methionine/valine (M/V) polymorphism (rs1799990) in the PRNP gene and the risk of Alzheimer disease: an update by meta-analysis | journal = Journal of the Neurological Sciences | volume = 326 | issue = 1–2 | pages = 89–95 | date = Mar 2013 | pmid = 23399523 | doi = 10.1016/j.jns.2013.01.020 }}</ref> Variant V [[allele]] carriers (VV and MV) show a 13% decreased risk with respect to developing Alzheimer’s compared to the methionine [[homozygote]] (MM). However, the protective effects of variant V carriers have been found exclusively in [[Caucasian race|Caucasians]]. The decreased risk in V allele carriers is further limited to late-onset Alzheimer's disease only (≥ 65 years).<ref name="He_2013" /> PRNP can also functionally interact with polymorphisms in two other genes implicated in Alzheimer's, [[PSEN1]] and [[Apolipoprotein E|APOE]], to compound risk for both Alzheimer’s and [[Creutzfeldt–Jakob disease|sporadic Creutzfeldt–Jakob disease]].<ref name="Laurén_2014" /> A [[point mutation]] on codon 102 of ''PRNP'' at least in part contributed to three separate patients' atypical [[frontotemporal dementia]] within the same family, suggesting a new phenotype for [[Gerstmann–Sträussler–Scheinker syndrome]].<ref name="Laurén_2014" /><ref name="Giovagnoli_2008">{{cite journal | vauthors = Giovagnoli AR, Di Fede G, Aresi A, Reati F, Rossi G, Tagliavini F | title = Atypical frontotemporal dementia as a new clinical phenotype of Gerstmann-Straussler-Scheinker disease with the PrP-P102L mutation. Description of a previously unreported Italian family | journal = Neurological Sciences | volume = 29 | issue = 6 | pages = 405–10 | date = December 2008 | pmid = 19030774 | doi = 10.1007/s10072-008-1025-z }}</ref> The same study proposed sequencing ''PRNP'' in cases of ambiguously diagnosed dementia, as the various forms of [[dementia]] can prove challenging to [[Differential diagnosis|differentially diagnose]].<ref name="Giovagnoli_2008" />