Novel proteostasis reporter mouse reveals different effects of cytoplasmic and nuclear aggregates on protein quality control in neurons

Abstract

The cellular protein quality control machinery is important for preventing protein misfolding and aggregation, and decline in protein homeostasis (proteostasis) is believed to play a crucial role in age-related neurodegenerative disorders. However, how proteostasis capacity of neurons 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), a conformationally unstable protein that requires chaperones for proper folding and sensitively 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 impairment in proteostasis in tauopathy mice, but not in Huntington’s disease mice. Mechanistic investigations in primary neuronal cultures demonstrate that cytoplasmic, but not nuclear, aggregates cause defects of cellular protein quality control. Thus, the Fluc-EGFP reporter mice enable new insights into proteostasis alterations in different diseases.

Loss of MTCH-1 suppresses age-related proteostasis collapse through the inhibition of programmed cell death factors

“…2 Although the PN robustly safeguards the proteome early in life, the capacity of the PN to maintain proteostasis declines abruptly during adulthood in worms, flies, and mice, leaving cells and tissues more vulnerable to the accumulation of toxic protein species with age. [4][5][6][7] Attempts to understand the basis of proteostasis collapse in the nematode worm Caenorhabditis elegans have revealed that proteostasis capacity declines as animals commit to reproductive maturity. 8,9 This is preceded by a rapid decline in the ability of the transcription factor HSF-1 to drive the expression of PN genes, most notably those encoding for small heat shock proteins (sHSPs) and HSP-70 family members.…”