Essential clock gene plays key role in neuroprotective pathways

A new study offers deeper insight into how a neuroprotective pathway is regulated both by temperature and the body clock.

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, researchers in the Department of Brain Sciences 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 involved in maintaining body temperature in cold environments. Rbm3 has also previously been shown to protect the brain against damage associated with neurodegenerative diseases such as Alzheimer's disease.

"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." Dr Marco Brancaccio Department of Brain Sciences

The researchers found that changes in temperature affected the protein's activity, and that the induction of Rbm3 relies on a 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 Marco Brancaccio, Lecturer in Dementia Research at the Department of Brain Sciences said: "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.”

The body clock and genetics

The body clock is underpinned by specialised genes, called clock genes, which are responsible for the daily fluctuations in physiology and behaviour including, but not limited, to the sleep-wake cycle.

These 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 do not work effectively in neurodegenerative disease. Dr. Brancaccio’s team set out to understand how clock timing and temperature are integrated to maintain homeostasis in the brain.

This study identifies that the Bmal1 protein as an important integrator between circadian function, and temperature sensing. The results could provide new therapeutic options to improve the protective function in the brain of Rbm3.

Dr Marieke Hekstra formerly the UK DRI at Imperial and now at the VIB-KU Leuven Center for Brain & Disease Research 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.”

Hoekstra M, Ness N, Badia Soteras A, Brancaccio Met al., 2024, Bmal1 integrates circadian function and temperature sensing in the suprachiasmatic nucleus, Proceedings of the National Academy of Sciences of USA, ISSN: 0027-8424

This article has been adapted from materials provided by the UK DRI