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

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

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

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Resumen

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.

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