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The project leading to these results received funding from the la Caixa Foundation (ID 100010434) under the agreement LCF/PR/HR19/52160007, HR18-00452 to I.F. We thank CERCA Programme/Generalitat de Catalunya for institutional support. The Proteomics Platform of Navarrabiomed is a member of Proteored (PRB3-ISCIII), and is supported by grant PT17/0019/009 to J.F.I., of the PE I+D+I 2013-2016 funded by ISCIII and FEDER. Part of this work was funded by a grant from the Spanish Ministry of Science Innovation and Universities (Ref. PID2019-110356RB-I00) to J.F.I. and E.S., and the Department of Economic and Business Development of the Government of Navarra (Ref. 0011-1411-2020-000028) to ES.

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Del Rio, JaAuthor
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Article

Dysregulated Brain Protein Phosphorylation Linked to Increased Human Tau Expression in the hTau Transgenic Mouse Model

Publicated to:International Journal Of Molecular Sciences. 23 (12): 6427- - 2022-06-01 23(12), DOI: 10.3390/ijms23126427

Authors: Ferrer, I; Andres-Benito, P; Ausin, K; Cartas-Cejudo, P; Lachen-Montes, M; del Rio, JA; Fernandez-Irigoyen, J; Santamaria, E

Affiliations

Barcelona Inst Sci & Technol, Inst Bioengn Catalonia IBEC Sci Pk Barcelona PCB, Mol & Cellular Neurobiotechnol, Barcelona 08028, Spain - Author
Bellvitge Univ Hosp, Bellvitge Biomed Res Inst IDIBELL, Calle Feixa Llarga sn, Barcelona 08907, Spain - Author
Institute for Bioengineering of Catalonia - Author
Molecular and Cellular Neurobiotechnology. Institute for Bioengineering of Catalonia - Author
Univ Barcelona, Dept Cell Biol Physiol & Immunol, Fac Biol, Carrer Baldiri Reixac, Barcelona 08028, Spain - Author
Univ Barcelona, Inst Hlth Carlos 3, Dept Pathol & Expt Therapeut, Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Barcelona 08907, Spain - Author
Univ Publ Navarra UPNA, Hosp Univ Navarra HUN, Clin Neuroprote Unit, Navarrabiomed,IdiSNA, Irunlarrea St, Pamplona 31192, Spain - Author
Univ Publ Navarra UPNA, Hosp Univ Navarra HUN, Prote Platform, Navarrabiomed,IdiSNA, Pamplona 31192, Spain - Author
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Abstract

Altered protein phosphorylation is a major pathologic modification in tauopathies and Alzheimer's disease (AD) linked to abnormal tau fibrillar deposits in neurofibrillary tangles (NFTs) and pre-tangles and beta-amyloid deposits in AD. hTau transgenic mice, which express 3R and less 4R human tau with no mutations in a murine knock-out background, show increased tau deposition in neurons but not NFTs and pre-tangles at the age of nine months. Label-free (phospho)proteomics and SWATH-MS identified 2065 proteins in hTau and wild-type (WT) mice. Only six proteins showed increased levels in hTau; no proteins were down-regulated. Increased tau phosphorylation in hTau was detected at Ser199, Ser202, Ser214, Ser396, Ser400, Thr403, Ser404, Ser413, Ser416, Ser422, Ser491, and Ser494, in addition to Thr181, Thr231, Ser396/Ser404, but not at Ser202/Thr205. In addition, 4578 phosphopeptides (corresponding to 1622 phosphoproteins) were identified in hTau and WT mice; 64 proteins were differentially phosphorylated in hTau. Sixty proteins were grouped into components of membranes, membrane signaling, synapses, vesicles, cytoskeleton, DNA/RNA/protein metabolism, ubiquitin/proteasome system, cholesterol and lipid metabolism, and cell signaling. These results showed that over-expression of human tau without pre-tangle and NFT formation preferentially triggers an imbalance in the phosphorylation profile of specific proteins involved in the cytoskeletal-membrane-signaling axis.

Keywords
cytoskeletonhtaumembranephosphorylationsynapsistauAggregationAlzheimers-diseaseAnimal-modelsCytoskeletonHtauMembraneMiceNetworksPathologyPhosphoproteome analysisPhosphorylationSynapsisTauTauopathiesTauopathy

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal International Journal Of Molecular Sciences due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2022, it was in position 66/285, thus managing to position itself as a Q1 (Primer Cuartil), in the category Biochemistry & Molecular Biology.

Independientemente del impacto esperado determinado por el canal de difusión, es importante destacar el impacto real observado de la propia aportación.

Según las diferentes agencias de indexación, el número de citas acumuladas por esta publicación hasta la fecha 2025-05-21:

  • Scopus: 2
  • OpenCitations: 3
Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-05-21:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 15.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 15 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 10.25.
  • The number of mentions on the social network X (formerly Twitter): 2 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.
  • Assignment of a Handle/URN as an identifier within the deposit in the Institutional Repository: http://hdl.handle.net/2445/187446