Colder temperatures help cells to clear toxic proteins tied to ALS
Study finds cold activates proteasome, a 'garbage disposal' complex within cells
Cold temperatures can activate a complex called the proteasome that cells use to clear themselves of unneeded proteins, including the protein clumps associated with amyotrophic lateral sclerosis (ALS), a new study reports.
In cell models of the disease, exposure to cold temperatures for a prolonged time significantly lowered the amount of these toxic proteins, and cold extended the lifespan of worms in an ALS model.
“Taken together, these results show how over the course of evolution, cold has preserved its influence on proteasome regulation — with therapeutic implications for aging and aging-associated diseases,” David Vilchez, PhD, a professor at the University of Cologne and the study’s lead author, said in a press release.
The study, “Cold temperature extends longevity and prevents disease-related protein aggregation through PA28γ-induced proteasomes,” was published in Nature Aging.
Protein clumps are a feature of aging and diseases like ALS
While large changes in body temperature can be seriously detrimental to health, abundant research done over the past century has shown that a small decrease in body temperature helps to prolong survival across organisms, from worms to fish to mice.
The biological mechanisms tying cooler body temperatures with prolonged survival, however, are poorly understood.
Aging is an extremely complicated process, with many biological changes that accrue as a person gets older. One common feature in aging is the formation of abnormal clumps of proteins inside of cells. Protein clumps also are a particular feature of ALS and other neurological disorders, which are generally more common among older individuals.
Given the connections between protein clumps and aging-related disorders, and between colder temperatures and longevity, a team of researchers in Germany hypothesized that cold temperatures might help to remove toxic protein aggregates by activating the proteasome — the molecular “garbage disposal” system cells use to eliminate unneeded proteins.
Through experiments in nematode worms (Caenorhabditis elegans, a common research model), the researchers showed that the proteasome is more active at cooler temperatures. This specifically was evident for the trypsin-like proteasome, but not other for components of this waste-disposal system.
Low temperatures triggered the activity of a proteasome-activating protein called PSME3 (also called PA28gamma), which is less active at warmer temperatures, the scientists reported.
Greater proteasome activity with cold in ALS-associated proteins
Blocking PSME3 activity at cold temperatures also blocked an increase in proteasome activation and shortened the worms’ lifespan, whereas higher PSME3 levels at cold temperatures activated the proteasome and increased longevity. Increasing the PSME3’s activity at warmer temperatures, however, reduced longevity.
“These results suggest a trade-off between the effects of PSME-3 in lifespan and protein aggregation when temperature rises … which is neutralized by cold temperature,” the researchers wrote.
Collectively, these findings lend credence to the idea that cold temperatures might promote a longer lifespan in part through proteasome activation, the scientists noted.
Researchers next tested the effects of cold temperatures on disease-associated proteins.
Specifically, they worked in models engineered to express mutated forms of the FUS or TDP-43 proteins, whose clumps are disease-driving in some ALS cases, and in models expressing polyQ peptide, the protein that characteristically forms abnormal clumps in Huntington’s disease.
For all of these disease-associated proteins, results showed less toxic clump formation at lower temperatures. This effect was diminished when PSME3 levels were lowered — but with increased levels, the protein-clearing effect of cold temperature also increased.
“Collectively, our data indicate that cold-induced [PMSE3] can attenuate the pathological [disease-driving] aggregation of distinct disease-related proteins in C. elegans models,” the researchers wrote.
Additional cellular experiments suggested that this same molecular mechanism is found in human cells.
“Importantly, the cold-induced role of PSME3 to diminish protein aggregation is also conserved in human cells, indicating that cold temperature could be a converging mechanism to prevent distinct human disorders with age,” the scientists concluded.
“We believe that these results may be applied to other age-related neurodegenerative diseases as well as to other animal species,” Vilchez said.
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