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

Sonja Blumenstock, Elena Katharina Schulz-Trieglaff, Kerstin Voelkl, Anna-Lena Bolender, Paul Lapios, Jana Lindner, Mark S. Hipp, F. Ulrich Hartl, Rudiger Klein, Irina Dudanova*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    3 Citations (Scopus)
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    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.

    Original languageEnglish
    Article number107260
    Number of pages15
    JournalEMBO Journal
    Volume40
    Issue number19
    DOIs
    Publication statusPublished - 1-Oct-2021

    Keywords

    • Huntington's disease
    • nuclear and cytoplasmic aggregates
    • protein homeostasis
    • reporter mouse
    • tauopathy
    • MOUSE MODEL
    • MUTANT HUNTINGTIN
    • PROTEIN AGGREGATION
    • INTRANUCLEAR INCLUSIONS
    • ENDOPLASMIC-RETICULUM
    • CHEMICAL CHAPERONE
    • CORTICAL-NEURONS
    • POLYQ PROTEINS
    • MOTOR-NEURONS
    • CELL-DEATH

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