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Once liberated, this N1 fragment acts neuroprotective in ischemic conditions and interferes with toxic peptides associated with neurodegenerative diseases, such as amyloid-beta (A\u03b2) in Alzheimer\u2019s disease. Since analog protective effects of N1 in prion diseases, such as Creutzfeldt-Jakob disease, have not been studied, and given that the protease releasing N1 has not been identified to date, we have generated and characterized transgenic mice overexpressing N1 (TgN1). Upon intracerebral inoculation of TgN1 mice with prions, no protective effects were observed at the levels of survival, clinical course, neuropathological, or molecular assessment. Likewise, primary neurons of these mice did not show protection against A\u03b2 toxicity. Our biochemical and morphological analyses revealed that this lack of protective effects is seemingly due to an impaired ER translocation of the disordered N1 resulting in its cytosolic retention with an uncleaved signal peptide. Thus, TgN1 mice represent the first animal model to prove the inefficient ER translocation of intrinsically disordered domains (IDD). In contrast to earlier studies, our data challenge roles of cytoplasmic N1 as a cell penetrating peptide or as a potent \u201canti-prion\u201d agent. Lastly, our study highlights both the importance of structured domains in the nascent chain for proteins to be translocated and aspects to be considered when devising novel N1-based therapeutic approaches against neurodegenerative diseases.<\/jats:p>","DOI":"10.1007\/s12035-020-01917-2","type":"journal-article","created":{"date-parts":[[2020,5,4]],"date-time":"2020-05-04T07:02:33Z","timestamp":1588575753000},"page":"2812-2829","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Transgenic Overexpression of the Disordered Prion Protein N1 Fragment in Mice Does Not Protect Against Neurodegenerative Diseases Due to Impaired ER Translocation"],"prefix":"10.1007","volume":"57","author":[{"given":"Behnam","family":"Mohammadi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4680-7622","authenticated-orcid":false,"given":"Luise","family":"Linsenmeier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4974-8955","authenticated-orcid":false,"given":"Mohsin","family":"Shafiq","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2255-8393","authenticated-orcid":false,"given":"Berta","family":"Puig","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2697-2364","authenticated-orcid":false,"given":"Giovanna","family":"Galliciotti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camilla","family":"Giudici","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Willem","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Eden","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1730-6674","authenticated-orcid":false,"given":"Friedrich","family":"Koch-Nolte","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Hsuan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5017-5528","authenticated-orcid":false,"given":"J\u00f6rg","family":"Tatzelt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7720-8817","authenticated-orcid":false,"given":"Markus","family":"Glatzel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9439-6533","authenticated-orcid":false,"given":"Hermann C.","family":"Altmeppen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,5,4]]},"reference":[{"issue":"2","key":"1917_CR1","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/S0014-5793(97)00920-4","volume":"413","author":"R Riek","year":"1997","unstructured":"Riek R, Hornemann S, Wider G, Glockshuber R, W\u00fcthrich K (1997) NMR characterization of the full-length recombinant murine prion protein, mPrP(23-231). 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