News from the MacAulay Lab

We have known for centuries that our brains are full of water – which was at some point in time even considered to contain our soul. The brain water is replenished at a rate of 500 ml water daily. But we barely understand how!

Since the stone age, surgeons have relieved elevated intracranial pressure (too much water in the brain) by cutting a hole in the skull. The level of refinement has obviously improved over the centuries, but the principle is the same. Crazy – isn’t it?

We must resolve the molecular mechanisms of how water enters into the brain – in order to therapeutically slow down these processes in pathologies involving too much brain water and speed them up in those involving too little brain water.

For those interested in the finer details of brain secretion, please click here. For those who just want a quick glimpse into the fascinating world of brain water transport, read the poem on the image.

Thanks to all the funding agencies who support our work on BrainH2O – absolutely essential for our path towards pharmacological treatment of these clinically challenging pathologies.

Traumatic brain injury and brain hemorrhage can lead to the brain water accumulation called hydrocephalus. The subsequent elevation in brain pressure can be fatal if left untreated. But we do not know how and why it happens and we have no efficient pharmacological treatment.

We are excited to share the molecular coupling between brain bleeding and brain water accumulation – either on verse here or on BioRxiv (find link in commentaries below). We hope this first stepping stone can bring us closer to medical treatment of this condition.  

Congratulations to Trine for her accomplishment with this study and thanks to all our collaborators. The generous funding from LBF and NNF is highly appreciated

To manage intracranial pressure in pathology, we must understand brain fluid dynamics in physiology

Finally – a F2F conference!

Thanks to all the participants at the BrainH2O symposium in Copenhagen this past week. It was wonderful to see colleagues and friends from around the world again – and to share the science that we envision will help diagnose and treat the patients with disturbed brain fluid balance.

Thanks to the Novo Nordic Foundation and the graduate school at SUND for their support.

It has remained elusive what opens the Pannexin 1 large pore channel – and what permeates the channel when open. In this study from the MacAulay laboratory, we – by rigorous and comparative experiments in different cell types – demonstrate that an open channel is not just a hole that allows all molecules of a given size to enter. Pannexin 1, like its cousins the connexions hemichannels, is indeed able to act as a gated and selective channel. See publication and read the commentary in Journal of Physiology.

When cells swell, the ion channel TRPV4 opens. But we did not know why! The MacAulay laboratory publishes a study in JBC revealing that TRPV4 – in some cell types – is able to directly sense the cell expansion by means of its most distal N-terminus and. 

It has been highly controversial in the connexin field what can permeate an open Cx43 hemichannel. The MacAulay laboratory publishes a study in Journal of Biological Chemistry on the structural determinants dictating that an open Cx43 hemichannel does not allow atomic ions to permeate: No Cx43 hemichannel-mediated ion conductance.

Professor Nanna MacAulay from Department of Neuroscience receives the Lundbeck Foundation’s Ascending Investigator Grant (5 mio. DKK) to determine the molecular mechanisms underlying sleep-induced regulation of the cerebrospinal fluid secretion.

The project has received10 mio. DKK from the Lundbeck Foundation’s thematic call: ‘What causes brain diseases’.

The MacAulay Laboratory is very excited to initiate this translational collaboration with clinicians Professor Rigmor H. Jensen, the headache center, Glostrup-Rigshospitalet, DK and Professor Alexandra Sinclair, Birmingham University, UK, who are both leading experts in the clinical aspects of this puzzling disease where young, obese females experience debilitating elevations in intracranial pressure. With an additional experimental ‘arm’ governed by transcriptomics expert Associate Professor Tune H. Pers and metobolomics expert Associate Professor Matthew Gillum, both from Novo Nordic Center for Basic Metabolic Research, University of Copenhagen, we will resolve the molecular mechanisms signifying the etiology of this disease - with the vision to create future pharmacological therapy to aid this growing patient group, for which no efficient treatment currently exists.

Thanks to the Lundbeck Foundation for their generous support of our research!

The MacAulay laboratory’s recent discovery of a role for cotransporters in brain fluid dynamics was covered in an issue of Newsweek, see article. The study revealed a novel form of fluid transport underlying the elusive formation of half a liter of brain water each day in the adult human. With this new finding, researchers have a first molecular handle to initiate rational pharmacological targeting of the brain fluid secretory machinery in diseases with disturbed brain water dynamics and disabling elevated intracranial pressure, such as hydrocephalus, stroke, traumatic brain injury, and brain tumors. The MacAulay laboratory is committed to resolving the intricate mechanisms and regulatory pathways governing our brain’s fluid management.

Thanks to the funding agencies that supported the research underlying these important findings (i.e. the Novo Nordic Foundation, the Independent Research Fund Denmark, Thorberg’s Foundation)