====== 14-3-3 protein ======

14-3-3 [[protein]]s were originally discovered as a family of proteins that are highly expressed in the brain. Through interactions with a multitude of binding partners, 14-3-3 proteins impact many aspects of brain function including neural signaling, neuronal development, and neuroprotection.
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Reincke et al. performed [[exome sequencing]] of 10 [[corticotroph adenoma]]s. They found [[somatic mutation]]s in the [[USP8]] [[deubiquitinase]] gene in 4 of 10 adenomas. The mutations clustered in the [[14-3-3 protein]] binding [[motif]] and enhanced the [[proteolysis]] [[cleavage]] and [[catalytic activity]] of USP8. Cleavage of USP8 led to increased deubiqutination of the EGF receptor, impairing its downregulation and sustaining EGF signaling. USP8 mutants enhanced promoter activity of the gene encoding proopiomelanocortin. In summary, our data show that dominant mutations in USP8 cause Cushing's disease via activation of EGF receptor signaling
((Reincke M, Sbiera S, Hayakawa A, Theodoropoulou M, Osswald A, Beuschlein F, Meitinger T, Mizuno-Yamasaki E, Kawaguchi K, Saeki Y, Tanaka K, Wieland T, Graf E, Saeger W, Ronchi CL, Allolio B, Buchfelder M, Strom TM, Fassnacht M, Komada M. Mutations in the deubiquitinase gene USP8 cause Cushing's disease. Nat Genet. 2015 Jan;47(1):31-8. doi: 10.1038/ng.3166. Epub 2014 Dec 8. PMID: 25485838.)).
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There is no practical and reliable premortem test for [[Creutzfeldt-Jakob disease]] and the related transmissible spongiform encephalopathies. Two proteins designated 130 and 131, which have been detected in low concentrations in [[cerebrospinal fluid]] from patients with Creutzfeldt-Jakob disease, appear to be sensitive and specific markers for the disease. Attempts to identify these proteins, however, have been unsuccessful. 
Hsich et al. detected proteins 130 and 131 in the normal human brains, partially sequenced their [[amino acid]]s and found that they matched the brain protein known as 14-3-3. They then developed a simple, rapid immunoassay for this protein and tested it in cerebrospinal fluid samples from 71 humans and 30 animals with spongiform encephalopathies and in control samples from 186 humans and 94 animals.

The immunoassay detected the 14-3-3 protein in cerebrospinal fluid from 68 of the 71 patients with Creutzfeldt-Jakob disease (96 percent, 95 percent confidence interval, 92 to 99 percent). Among 94 patients with other dementias, the specificity was 96 percent. If one excludes the three patients with dementia who had strokes within one month before testing, the specificity was 99 percent. The test was positive in 12 of 24 patients with viral encephalitis. In animals, the sensitivity of the assay was 87 percent and the specificity was 99 percent.

In patients with [[dementia]], a positive [[immunoassay]] for the 14-3-3 brain protein in [[cerebrospinal fluid]] strongly supports a diagnosis of [[Creutzfeldt-Jakob disease]]. This finding, however, does not support the use of the test in patients without clinically evident dementia
((Hsich G, Kenney K, Gibbs CJ, Lee KH, Harrington MG. The 14-3-3 brain protein in cerebrospinal fluid as a marker for transmissible spongiform encephalopathies. N Engl J Med. 1996 Sep 26;335(13):924-30. doi: 10.1056/NEJM199609263351303. PMID: 8782499.))