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  Fluc-EGFP reporter mice reveal differential alterations of neuronal proteostasis in aging and disease

Blumenstock, S., Schulz-Trieglaff, K., Voelkl, K., Bolender, A.-L., Lapios, P., Lindner, J., et al. (2021). Fluc-EGFP reporter mice reveal differential alterations of neuronal proteostasis in aging and disease. EMBO Journal, 40(19): e107260. doi:10.15252/embj.2020107260.

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© 2021 The Authors. Open Access funding enabled and organized by Projekt DEAL.
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 Creators:
Blumenstock, Sonja1, Author              
Schulz-Trieglaff, Katharina1, Author              
Voelkl, Kerstin1, Author              
Bolender, Anna-Lena1, Author              
Lapios, Paul1, Author
Lindner, Jana1, Author              
Hipp, Mark S.2, Author              
Hartl, F. Ulrich2, Author              
Klein, Rüdiger1, Author              
Dudanova, Irina3, Author              
Affiliations:
1Department: Molecules-Signaling-Development / Klein, MPI of Neurobiology, Max Planck Society, ou_1113546              
2Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565152              
3Research Group: Molecular Neurodegeneration / Dudanova, MPI of Neurobiology, Max Planck Society, ou_3060199              

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Free keywords: MOUSE MODEL; MUTANT HUNTINGTIN; PROTEIN AGGREGATION; INTRANUCLEAR INCLUSIONS; ENDOPLASMIC-RETICULUM; CHEMICAL CHAPERONE; CORTICAL-NEURONS; POLYQ PROTEINS; MOTOR-NEURONS; CELL-DEATHBiochemistry & Molecular Biology; Cell Biology; Huntington's disease; nuclear and cytoplasmic aggregates; protein homeostasis; reporter mouse; tauopathy;
 Abstract: The cellular protein quality control machinery is important for preventing protein misfolding and aggregation. Declining protein homeostasis (proteostasis) is believed to play a crucial role in age-related neurodegenerative disorders. However, how neuronal proteostasis capacity changes in different diseases is not yet sufficiently understood, and progress in this area has been hampered by the lack of tools to monitor proteostasis in mammalian models. Here, we have developed reporter mice for in vivo analysis of neuronal proteostasis. The mice express EGFP-fused firefly luciferase (Fluc-EGFP), a conformationally unstable protein that requires chaperones for proper folding, and that reacts to proteotoxic stress by formation of intracellular Fluc-EGFP foci and by reduced luciferase activity. Using these mice, we provide evidence for proteostasis decline in the aging brain. Moreover, we find a marked reaction of the Fluc-EGFP sensor in a mouse model of tauopathy, but not in mouse models of Huntington's disease. Mechanistic investigations in primary neuronal cultures demonstrate that different types of protein aggregates have distinct effects on the cellular protein quality control. Thus, Fluc-EGFP reporter mice enable new insights into proteostasis alterations in different diseases.

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Language(s): eng - English
 Dates: 2021
 Publication Status: Published online
 Pages: 15
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000703017600008
DOI: 10.15252/embj.2020107260
 Degree: -

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Project name : Toxic Protein Aggregation in Neurodegeneration (ToPAG)
Grant ID : 318987
Funding program : Funding Programme 7 (FP7)
Funding organization : European Commission (EC)

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Title: EMBO Journal
  Other : EMBO J.
Source Genre: Journal
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Publ. Info: Nature Publishing Group
Pages: - Volume / Issue: 40 (19) Sequence Number: e107260 Start / End Page: - Identifier: ISSN: 0261-4189
CoNE: https://pure.mpg.de/cone/journals/resource/954925497061