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We find that replacement of the average efficiency signal sequence of PrP with more efficient signals rescues mice from neurodegeneration caused by otherwise pathogenic PrP mutants in a downstream hydrophobic domain (HD). This effect is explained by the demonstration that efficient signal sequence function precludes generation of a cytosolically exposed, disease-causing transmembrane form of PrP mediated by the HD mutants. Thus, signal sequences are functionally nonequivalent in vivo, with intrinsic inefficiency of the native PrP signal being required for pathogenesis of a subset of disease-causing PrP mutations.<\/jats:p>","DOI":"10.1083\/jcb.200911115","type":"journal-article","created":{"date-parts":[[2010,2,15]],"date-time":"2010-02-15T20:58:38Z","timestamp":1266267518000},"page":"515-526","update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":76,"title":["Signal sequence insufficiency contributes to neurodegeneration caused by transmembrane prion protein"],"prefix":"10.1083","volume":"188","author":[{"given":"Neena S.","family":"Rane","sequence":"first","affiliation":[{"name":"Cell Biology and Metabolism Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oishee","family":"Chakrabarti","sequence":"additional","affiliation":[{"name":"Cell Biology and Metabolism Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lionel","family":"Feigenbaum","sequence":"additional","affiliation":[{"name":"Laboratory of Animal Sciences, National Cancer Institute, Frederick, MD 21702 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramanujan S.","family":"Hegde","sequence":"additional","affiliation":[{"name":"Cell Biology and Metabolism Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2010,2,15]]},"reference":[{"key":"2023072905080883700_bib1","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1083\/jcb.200207030","article-title":"Mitochondrial targeting and a novel transmembrane arrest of Alzheimer\u2019s amyloid precursor protein impairs mitochondrial function in neuronal cells","volume":"161","author":"Anandatheerthavarada","year":"2003","journal-title":"J. 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