{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nDoppel, the protein product of the PRND gene, is expressed primarily in the male reproductive system. In human tissues it is localized to Sertoli cells, mature spermatozoa and seminal plasma, suggesting an important role in spermatogenesis and acrosome biogenesis, which is essential for male fertility. Additionally, studies in several mammalian species indicate that Doppel is produced early during testicular development, with a cellular distribution in both germ and Sertoli cells, supporting its contribution to normal testicular function and fertility regulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic analyses have revealed that polymorphisms in PRND are associated with neurodegenerative phenotypes. Several independent studies have identified single nucleotide polymorphisms—including variants at codon 174 and within the 3′ untranslated region—as well as haplotypic differences, with associations reported in sporadic Creutzfeldt-Jakob disease and in Alzheimer’s disease, where the risk and age at onset appear to be influenced by the genotype. Moreover, microsatellite analyses of the prion gene complex indicate that homozygous PRND allelic configurations may contribute to disease susceptibility. Together, these findings suggest that, although Doppel itself may not directly drive prion propagation, its genetic variants might modulate the risk or progression of neurodegenerative disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its physiological role in reproduction and genetic links to neurodegenerative diseases, Doppel has been implicated in cellular interactions and pathophysiological processes. In neuronal cell models, Doppel can interact with the cellular prion protein (PrP^C) and co-localize on plasma membrane domains, yet lacks binding to some of the canonical PrP^C partners. Functionally, overexpression of Doppel in neural cell lines induces cytotoxicity through apoptotic mechanisms that are antagonized by full-length PrP^C and modulated by copper ions, suggesting an antagonistic interplay. Moreover, aberrant expression of Doppel in tumor microenvironments—such as in astrocytomas and tumor endothelial cells—has been linked to changes in tumor cell migration, angiogenesis, and altered receptor signaling (e.g. VEGFR2 modulation), indicating a potential role in tumor progression. Finally, interaction studies have identified binding of Doppel to the 37 kDa/67 kDa laminin receptor, although its binding properties differ from PrP^C, further emphasizing its distinct, multifaceted role in both neural and tumor cell contexts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Katell Peoc'h, Catherine Serres, Yveline Frobert, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The human \"prion-like\" protein Doppel is expressed in both Sertoli cells and spermatozoa."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M206357200"}], "href": "https://doi.org/10.1074/jbc.M206357200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12200435"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12200435"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "C Serres, K Peoc'h, A M Courtot, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Spatio-developmental distribution of the prion-like protein doppel in Mammalian testis: a comparative analysis focusing on its presence in the acrosome of spermatids."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biol Reprod (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1095/biolreprod.105.047829"}], "href": "https://doi.org/10.1095/biolreprod.105.047829"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16421231"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16421231"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Alberto Azzalin, Igor Del Vecchio, Luca Ferretti, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The prion-like protein Doppel (Dpl) interacts with the human receptor for activated C-kinase 1 (RACK1) protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Anticancer Res (2006)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17201176"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17201176"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "B Schröder, B Franz, P Hempfling, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Polymorphisms within the prion-like protein gene (Prnd) and their implications in human prion diseases, Alzheimer's disease and other neurological disorders."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Genet (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s004390100591"}], "href": "https://doi.org/10.1007/s004390100591"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11702213"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11702213"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "K Peoc'h, H Volland, A De Gassart, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Prion-like protein Doppel expression is not modified in scrapie-infected cells and in the brains of patients with Creutzfeldt-Jakob disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0014-5793(03)00012-7"}], "href": "https://doi.org/10.1016/s0014-5793(03"}, {"type": "t", "text": "00012-7) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12586339"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12586339"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "E Golanska, K Hulas-Bigoszewska, E Rutkiewicz, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Polymorphisms in the prion protein gene and in the doppel gene increase susceptibility for Creutzfeldt-Jakob disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Hum Genet (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.ejhg.5201161"}], "href": "https://doi.org/10.1038/sj.ejhg.5201161"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14970845"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14970845"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Byung-Hoon Jeong, Nam-Ho Kim, Eun-Kyoung Choi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Polymorphism at 3' UTR +28 of the prion-like protein gene is associated with sporadic Creutzfeldt-Jakob disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Hum Genet (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.ejhg.5201460"}], "href": "https://doi.org/10.1038/sj.ejhg.5201460"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15986038"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15986038"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Byung-Hoon Jeong, Nam-Ho Kim, Jae-Il Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Polymorphisms at codons 56 and 174 of the prion-like protein gene (PRND) are not associated with sporadic Creutzfeldt-Jakob disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Hum Genet (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10038-005-0254-8"}], "href": "https://doi.org/10.1007/s10038-005-0254-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15933804"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15933804"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Hermann Geldermann, Heinz Bartenschlager, Siegfried Preuss, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Human Doppel and prion protein share common membrane microdomains and internalization pathways."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Biochem Cell Biol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.biocel.2004.03.002"}], "href": "https://doi.org/10.1016/j.biocel.2004.03.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15203115"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15203115"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Shao-Man Yin, Man-Sun Sy, Huai-Yi Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Interaction of Doppel with the full-length laminin receptor precursor protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arch Biochem Biophys (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.abb.2004.06.003"}], "href": "https://doi.org/10.1016/j.abb.2004.06.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15246873"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15246873"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "S Comincini, V Ferrara, A Arias, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Diagnostic value of PRND gene expression profiles in astrocytomas: relationship to tumor grades of malignancy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Rep (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/or.17.5.989"}], "href": "https://doi.org/10.3892/or.17.5.989"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17390034"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17390034"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Ping Li, Jun Han, Bing Shan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "[Expression of recombinant human doppel protein and analysis of its cytotoxic activities]."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Bing Du Xue Bao (2007)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17894227"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17894227"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Ping Li, Chenfang Dong, Yanjun Lei, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Transient expressions of doppel and its structural analog prionDelta32-121 in SH-SY5Y cells caused cytotoxicity possibly by triggering similar apoptosis pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Rep (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s11033-009-9772-3"}], "href": "https://doi.org/10.1007/s11033-009-9772-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19728151"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19728151"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Marcin Flirski, Monika Sieruta, Ewa Golańska, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PRND 3'UTR polymorphism may be associated with behavioral disturbances in Alzheimer disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Prion (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4161/pri.6.1.18428"}], "href": "https://doi.org/10.4161/pri.6.1.18428"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22453181"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22453181"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Taslim A Al-Hilal, Seung Woo Chung, Jeong Uk Choi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Targeting prion-like protein doppel selectively suppresses tumor angiogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI83427"}], "href": "https://doi.org/10.1172/JCI83427"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26950422"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26950422"}]}]}]}