Fluc‐EGFP reporter mice reveal differential alterations of neuronal proteostasis in aging and disease. (19th August 2021)

• Record Type: Journal Article
• Authors: Blumenstock, Sonja; Schulz‐Trieglaff, Elena Katharina; Voelkl, Kerstin; Bolender, Anna‐Lena; Lapios, Paul; Lindner, Jana; Hipp, Mark S; Hartl, F Ulrich; Klein, Rüdiger; Dudanova, Irina
• Is Part Of: EMBO journal. Volume 40:Number 19(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-08-19
• Subjects: Huntington's disease -- nuclear and cytoplasmic aggregates -- protein homeostasis -- reporter mouse -- tauopathy; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2020107260
• Languages: English
• ISSNs: 0261-4189

Abstract

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. SYNOPSIS: This study describes a new reporter mouse line for monitoring neuronal proteostasis. The reporter reveals that protein aggregates associated with neurodegenerative diseases differ in their impact on the cellular protein quality control system. Fluc‐EGFP reporter mouse allows studying neuronal proteostasis alterations in aging and disease. Fluc‐EGFP reporter detects proteostasis impairments in tauopathy mice, but not in Huntington's disease mice. Mechanistic studies in cultured neurons show that different aggregating proteins cause distinct cellular compartment‐specific defects of proteostasis. Abstract : In vivo expression of conformationally unstable EGFP‐fused firefly luciferase, which forms intracellular foci and exhibits reduced activity upon proteotoxic stress, elucidates the occurrence of proteostasis decline in mouse models of aging and tauopathy but not Huntington's disease.