Proteomic analysis of hydromethylthionine in the line 66 model of frontotemporal dementia demonstrates actions on tau-dependent and tau-independent networks

Karima Schwab, Valeria Melis, Charles R. Harrington, Claude M. Wischik, Mandy Magbagbeolu, Franz Theuring, Gernot Riedel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number2162
Number of pages30
JournalCells
Volume10
Issue number8
DOIs
Publication statusPublished - 22 Aug 2021

Keywords

  • Frontotemporal dementia
  • Hydromethylthionine
  • LMTM
  • Mouse model
  • Proteomics
  • Tau protein

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