How temperature and circadian rhythms intersect to regulate a protein shown to protect against neurodegeneration

A new study led by Dr Marco Brancaccio (UK DRI at Imperial) and Dr Marieke Hoekstra (former UK DRI at Imperial, now VIB-KU Leuven Center for Brain & Disease Research) offers a deeper insight into how a neuroprotective pathway is regulated both by temperature and the body clock. This research, published in the journal PNAS, could open up new therapeutic avenues for neurodegenerative disease.

What was the challenge?

The body clock is underpinned by specialised genes, called clock genes, which are ultimately responsible for daily fluctuations in physiology and behaviour including, but not limited, to the sleep-wake cycle. These clock genes are resistant to temperature changes, which allows them to keep accurate daily timing. However, many pathways controlled by clock genes are also sensitive to temperature, and some of them are dysregulated in neurodegenerative disease. Dr Brancaccio’s team set out to understand how clock timing and temperature are integrated to maintain homeostasis in the brain.

What did the team do and what did they find?

The suprachiasmatic nucleus is the area of the brain which controls the body clock in mammals. Using tissue slices taken from the suprachiasmatic nucleus of mouse brains, the researchers looked at how pathways controlled by clock genes responded to temperature changes.

The team looked specifically at a protein called RNA Binding Motif 3 (Rbm3), which is controlled by clock genes, and known to be implicated in maintaining body temperature in cold environments. Rbm3 has also previously been shown to protect the brain against damage associated with neurodegenerative disease.

The researchers found that changes in temperature affected Rbm3’s activity, and that the induction of Rbm3 relies on a core clock protein called Bmal1. When Bmal1 levels were lowered, Rbm3’s responses to temperature changes were also disrupted, an effect that was accompanied by dysfunction in the suprachiasmatic nucleus.

Dr Hoekstra said:

“We showed that Rbm3 is affected both by temperature and daily rhythms. Because over-expression of this protein can protect against synapse loss and cognitive decline in a mouse model for neurodegeneration, our research could open up new opportunities for therapeutic targets.”

What is the impact of these findings?

The study identifies Bmal1 as an important integrator between circadian function, and temperature sensing. This could provide a new therapeutic route to bolster the neuroprotective function of Rbm3.

Dr Brancaccio explained:

“To our surprise, we have found that an essential clock gene, Bmal1, does not only play an essential role in circadian rhythm generation, but also in sensing and mediating temperature-dependent responses of downstream neuroprotective pathways. Of course, the body clock does not normally operate in a test tube, and so it will be critically important to understand how neurodegenerative processes impinge on it in the real world.

Our work suggests that a disconnect in the transmission of information between temperature-insensitive clock genes and temperature-sensitive clock-controlled pathways could be a point of weakness in the overall resilience of our body clock, with Bmal1 as a potential target for bolstering its function upon neurodegenerative insult.”

To find out more about Dr Marco Brancaccio’s research, visit his UK DRI profile. To keep up to date with the latest UK DRI news and events, sign up to receive our monthly newsletter.

Reference: Hoekstra MMB, Ness N, Badia-Soteras A, Brancaccio M. Bmal1 integrates circadian function and temperature sensing in the suprachiasmatic nucleus. Proc Natl Acad Sci U S A. 2024 Apr 23;121(17):e2316646121. doi: 10.1073/pnas.2316646121

Article published: 15 April 2024
Banner image: Shutterstock/Clare M