Proteomic Analysis of Hydromethylthionine in the Line 66 Model of Frontotemporal Dementia Demonstrates Actions on Tau-Dependent and Tau-Independent Networks
Abnormal aggregation of tau is the pathological hallmark of tauopathies including frontotemporal dementia (FTD). We have generated tau-transgenic mice that express the aggregation-prone P301S human tau (line 66). These mice present with early-onset, high tau load in brain and FTD-like behavioural de...
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MDPI AG
2021-08-01
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| author | Karima Schwab Valeria Melis Charles R. Harrington Claude M. Wischik Mandy Magbagbeolu Franz Theuring Gernot Riedel |
| author_facet | Karima Schwab Valeria Melis Charles R. Harrington Claude M. Wischik Mandy Magbagbeolu Franz Theuring Gernot Riedel |
| author_sort | Karima Schwab |
| collection | DOAJ |
| description | Abnormal aggregation of tau is the pathological hallmark of tauopathies including frontotemporal dementia (FTD). We have generated tau-transgenic mice that express the aggregation-prone P301S human tau (line 66). These mice present with early-onset, high tau load in brain and FTD-like behavioural deficiencies. Several of these behavioural phenotypes and tau pathology are reversed by treatment with hydromethylthionine but key pathways underlying these corrections remain elusive. In two proteomic experiments, line 66 mice were compared with wild-type mice and then vehicle and hydromethylthionine treatments of line 66 mice were compared. The brain proteome was investigated using two-dimensional electrophoresis and mass spectrometry to identify protein networks and pathways that were altered due to tau overexpression or modified by hydromethylthionine treatment. Overexpression of mutant tau induced metabolic/mitochondrial dysfunction, changes in synaptic transmission and in stress responses, and these functions were recovered by hydromethylthionine. Other pathways, such as NRF2, oxidative phosphorylation and protein ubiquitination were activated by hydromethylthionine, presumably independent of its function as a tau aggregation inhibitor. Our results suggest that hydromethylthionine recovers cellular activity in both a tau-dependent and a tau-independent fashion that could lead to a wide-spread improvement of homeostatic function in the FTD brain. |
| first_indexed | 2024-03-10T08:54:47Z |
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| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T08:54:47Z |
| publishDate | 2021-08-01 |
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| spelling | doaj.art-b2500fa0bdfa475ebc7bdc4d30a9d0762023-11-22T07:12:37ZengMDPI AGCells2073-44092021-08-01108216210.3390/cells10082162Proteomic Analysis of Hydromethylthionine in the Line 66 Model of Frontotemporal Dementia Demonstrates Actions on Tau-Dependent and Tau-Independent NetworksKarima Schwab0Valeria Melis1Charles R. Harrington2Claude M. Wischik3Mandy Magbagbeolu4Franz Theuring5Gernot Riedel6School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UKSchool of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UKSchool of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UKSchool of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UKCharité—Universitätsmedizin Berlin, Hessische Str. 3-4, 10115 Berlin, GermanyCharité—Universitätsmedizin Berlin, Hessische Str. 3-4, 10115 Berlin, GermanySchool of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UKAbnormal aggregation of tau is the pathological hallmark of tauopathies including frontotemporal dementia (FTD). We have generated tau-transgenic mice that express the aggregation-prone P301S human tau (line 66). These mice present with early-onset, high tau load in brain and FTD-like behavioural deficiencies. Several of these behavioural phenotypes and tau pathology are reversed by treatment with hydromethylthionine but key pathways underlying these corrections remain elusive. In two proteomic experiments, line 66 mice were compared with wild-type mice and then vehicle and hydromethylthionine treatments of line 66 mice were compared. The brain proteome was investigated using two-dimensional electrophoresis and mass spectrometry to identify protein networks and pathways that were altered due to tau overexpression or modified by hydromethylthionine treatment. Overexpression of mutant tau induced metabolic/mitochondrial dysfunction, changes in synaptic transmission and in stress responses, and these functions were recovered by hydromethylthionine. Other pathways, such as NRF2, oxidative phosphorylation and protein ubiquitination were activated by hydromethylthionine, presumably independent of its function as a tau aggregation inhibitor. Our results suggest that hydromethylthionine recovers cellular activity in both a tau-dependent and a tau-independent fashion that could lead to a wide-spread improvement of homeostatic function in the FTD brain.https://www.mdpi.com/2073-4409/10/8/2162mouse modeltau proteinfrontotemporal dementiaproteomicshydromethylthionineLMTM |
| spellingShingle | Karima Schwab Valeria Melis Charles R. Harrington Claude M. Wischik Mandy Magbagbeolu Franz Theuring Gernot Riedel Proteomic Analysis of Hydromethylthionine in the Line 66 Model of Frontotemporal Dementia Demonstrates Actions on Tau-Dependent and Tau-Independent Networks Cells mouse model tau protein frontotemporal dementia proteomics hydromethylthionine LMTM |
| title | Proteomic Analysis of Hydromethylthionine in the Line 66 Model of Frontotemporal Dementia Demonstrates Actions on Tau-Dependent and Tau-Independent Networks |
| title_full | Proteomic Analysis of Hydromethylthionine in the Line 66 Model of Frontotemporal Dementia Demonstrates Actions on Tau-Dependent and Tau-Independent Networks |
| title_fullStr | Proteomic Analysis of Hydromethylthionine in the Line 66 Model of Frontotemporal Dementia Demonstrates Actions on Tau-Dependent and Tau-Independent Networks |
| title_full_unstemmed | Proteomic Analysis of Hydromethylthionine in the Line 66 Model of Frontotemporal Dementia Demonstrates Actions on Tau-Dependent and Tau-Independent Networks |
| title_short | Proteomic Analysis of Hydromethylthionine in the Line 66 Model of Frontotemporal Dementia Demonstrates Actions on Tau-Dependent and Tau-Independent Networks |
| title_sort | proteomic analysis of hydromethylthionine in the line 66 model of frontotemporal dementia demonstrates actions on tau dependent and tau independent networks |
| topic | mouse model tau protein frontotemporal dementia proteomics hydromethylthionine LMTM |
| url | https://www.mdpi.com/2073-4409/10/8/2162 |
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