Thread by @TheVilchezLab

New work from the lab @NatureAging!❄️Lowering body temperature extends #longevity. We find that cold-induced #proteostasis prevents #aging and aggregation of proteins that cause age-related diseases #ALS #HuntingtonDisease in C. elegans and human cells nature.com/articles/s4358…

This was a tour de force by Hyun Ju Lee, @sedakoyuncu12, Hafiza Alirzayeva, @AlirezaBarandaq, and Amir Khodakarami (3 lab generations!). 1000x thanks to @impetusgrants for believing in us. Thanks to @CECAD_ @CGA_age @UniCologne @UKKoeln for their support

Aging is a major risk factor for neurodegenerative disorders linked with protein aggregation (#Alzheimers, #Parkinsonsdisease , #HuntingtonDisease, #ALS). We hypothesized that defining cold-induced changes can lead to converging modifiers of pathological protein aggregation🤔

We explored whether cold temperature influences proteasome activity, a machinery that can eliminate damaged proteins. We found that cold temperature induces the proteasome activator PA28γ/PSME3

Cold-induced PA28γ/PSME3 generates non-canonical proteasomes that degrade proteins in a ubiquitin-independent manner. Cold-induced PA28γ/PSME3 extends longevity and delays age-related deficits in C. elegans

Notably, cold-induced proteasomes prevent aggregation of disease-related proteins in C. elegans models of Huntington’s and ALS.
Then we asked whether this mechanism is evolutionary conserved in human cells

Normal human body temperature ranges between 36.5-37 °C. Whereas an acute drop in body temperature below 35 °C leads to hypothermia, the human body temperature slightly varies during the day and even reaches moderate cold temperatures (36 °C) during sleep

To explore whether a moderate cooling also influences proteasome activity in human cells, we shifted human cell lines and patient iPSC-derived neurons from standard temperature (37 °C) to moderate cold temperature (36 °C) for 24 hours

Exposure of human cells to moderate cold temperature (36 °C) also activates proteasome activity through PA28γ/PSME3, suppressing disease-related protein aggregation and neurodegeneration

Together, our findings reveal a beneficial role of cold temperature that crosses evolutionary boundaries with potential implications for multi-disease prevention. Here the link to a Research Briefing of our study
nature.com/articles/s4358…

Although there is still a lot to do to understand and fight #ALS, I dedicate this work to the memory of the late Carlos Pacheco (1960-2022): one of the most inspiring comic-book artists (@DolmenEditorial @PaniniComicsEsp @Marvel @DCComics)

And of course, this little contribution is also for one of my best friends that was diagnosed #ALS a few years ago. Keep fighting JLP!