Bonham, Luke W. and Steele, Natasha Z. R. and Karch, Celeste M. and Broce, Iris and Geier, Ethan G. and Wen, Natalie L. and Momeni, Parastoo and Hardy, John and Miller, Zachary A. and Gorno-Tempini, Maria Luisa and Hess, Christopher P. and Lewis, Patrick and Miller, Bruce L. and Seeley, William W. and Manzoni, Claudia and Desikan, Rahul S. and Baranzini, Sergio E. and Ferraris, Raffaele and Yokoyama, Jennifer S. and Hernandez, D. G. and Nalls, M. A. and Rohrer, J. D. and Ramasamy, A. and Kwok, J. B. J. and Dobson-Stone, C. and Schofield, P. R. and Halliday, G. M. and Hodges, J. R. and Piguet, O. and Bartley, L. and Thompson, E. and Haan, E. and Hernandez, I and Ruiz, A. and Boada, M. and Borroni, B. and Padovani, A. and Cruchaga, C. and Cairns, N. J. and Benussi, L. and Binetti, G. and Ghidoni, R. and Forloni, G. and Albani, D. and Galimberti, D. and Fenoglio, C. and Serpente, M. and Scarpini, E. and Clarimon, J. and Lleo, A. and Blesa, R. and Waldo, M. Landqvist and Nilsson, K. and Nilsson, C. and Mackenzie, I. R. A. and Hsiung, G-Y R. and Mann, D. M. A. and Grafman, J. and Morris, C. M. and Attems, J. and Griffiths, T. D. and McKeith, I. G. and Thomas, A. J. and Pietrini, P. and Huey, E. D. and Wassermann, E. M. and Baborie, A. and Jaros, E. and Tierney, M. C. and Pastor, P. and Razquin, C. and Ortega-Cubero, S. and Alonso, E. and Perneczky, R. and Diehl-Schmid, J. and Alexopoulos, P. and Kurz, A. and Rainero, I and Rubino, E. and Pinessi, L. and Rogaeva, E. and St George-Hyslop, P. and Rossi, G. and Tagliavini, F. and Giaccone, G. and Rowe, J. B. and Schlachetzki, J. C. M. and Uphill, J. and Collinge, J. and Mead, S. and Danek, A. and Van Deerlin, V. M. and Grossman, M. and Trojanowski, J. Q. and van der Zee, J. and Cruts, M. and Van Broeckhoven, C. and Cappa, S. F. and Leber, I and Hannequin, D. and Golfier, V and Vercelletto, M. and Brice, A. and Nacmias, B. and Sorbin, S. and Bagnoli, S. and Piaceri, I and Nielsen, J. E. and Hjermind, L. E. and Riemenschneider, M. and Mayhaus, M. and Ibach, B. and Gasparoni, G. and Pichler, S. and Gu, W. and Rossor, M. N. and Fox, N. C. and Warren, J. D. and Spillantini, M. G. and Morriss, H. R. and Rizzu, P. and Heutink, P. and Snowden, J. S. and Rollinson, S. and Richardson, A. and Gerhard, A. and Bruni, A. C. and Maletta, R. and Frangipane, F. and Cupidi, C. and Bernardi, L. and Anfossi, M. and Gallo, M. and Conidi, M. E. and Smirne, N. and Rademakers, R. and Baker, M. and Dickson, D. W. and Graff-Radford, N. R. and Petersen, R. C. and Knopman, D. and Josephs, K. A. and Boeve, B. F. and Parisi, J. E. and Karydas, A. M. and Rosen, H. and van Swieten, J. C. and Dopper, E. G. P. and Seelaar, H. and Pijnenburg, Y. A. L. and Scheltens, P. and Logroscino, G. and Capozzo, R. and Novelli, V and Puca, A. A. and Franceschi, M. and Postiglione, A. and Milan, G. and Sorrentino, P. and Kristiansen, M. and Chian, H-H and Graff, C. and Pasquier, F. and Rollin, A. and Deramecourt, V and Lebouvier, T. and Kapogiannis, D. and Ferrucci, L. and Pickering-Brown, S. and Singleton, A. B. (2019) Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia. SCIENTIFIC REPORTS, 9: 10854. ISSN 2045-2322,
Full text not available from this repository. (Request a copy)Abstract
The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA's relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death, x' working in combination to promote neurodegeneration.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | FRONTOTEMPORAL LOBAR DEGENERATION; HERITABILITY; DEMENTIA; MECHANISMS; SCLEROSIS; EXPANSION; SUBTYPES; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Psychiatrie und Psychotherapie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 02 Apr 2020 10:43 |
| Last Modified: | 02 Apr 2020 10:43 |
| URI: | https://pred.uni-regensburg.de/id/eprint/26602 |
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