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Journal Article

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

MPS-Authors
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Blumenstock,  Sonja
Department: Molecules-Signaling-Development / Klein, MPI of Neurobiology, Max Planck Society;
Research Group: Molecular Neurodegeneration / Dudanova, MPI of Neurobiology, Max Planck Society;

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Schulz-Trieglaff,  Elena Katharina
Department: Molecules-Signaling-Development / Klein, MPI of Neurobiology, Max Planck Society;

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Voelkl,  Kerstin
Department: Molecules-Signaling-Development / Klein, MPI of Neurobiology, Max Planck Society;
Research Group: Molecular Neurodegeneration / Dudanova, MPI of Neurobiology, Max Planck Society;

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Bolender,  Anna-Lena
Department: Molecules-Signaling-Development / Klein, MPI of Neurobiology, Max Planck Society;
Research Group: Molecular Neurodegeneration / Dudanova, MPI of Neurobiology, Max Planck Society;

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Lapios,  Paul
Department: Molecules-Signaling-Development / Klein, MPI of Neurobiology, Max Planck Society;
Research Group: Molecular Neurodegeneration / Dudanova, MPI of Neurobiology, Max Planck Society;

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Lindner,  Jana
Department: Molecules-Signaling-Development / Klein, MPI of Neurobiology, Max Planck Society;

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Hipp,  Mark S.
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

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Hartl,  F. Ulrich
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

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Klein,  Rüdiger
Department: Molecules-Signaling-Development / Klein, MPI of Neurobiology, Max Planck Society;

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Dudanova,  Irina
Research Group: Molecular Neurodegeneration / Dudanova, MPI of Neurobiology, Max Planck Society;
Department: Molecules-Signaling-Development / Klein, MPI of Neurobiology, Max Planck Society;

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Citation

Blumenstock, S., Schulz-Trieglaff, E. 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. The EMBO Journal, 40(19): e107260. doi:10.15252/embj.2020107260.


Cite as: https://hdl.handle.net/21.11116/0000-0009-AF46-4
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.