Molecular mechanism associated with neuronal death discovered

A study led by UB, IBMB-CSIC and CIBERNED has identified a crucial mechanism associated with neuronal death and motor changes in the most advanced mammals, which may help combat neurodegenerative diseases.

Wednesday, February 7, 2024

The human brain is an organ that consumes 20 to 25% of the energy needed by the entire body. This high energy requirement for neuronal function depends on the transport and precise distribution of mitochondria—the energy-generating cellular organelles—in each neuron.

Now a study published in the journal Scientific alarm identifies for the first time a molecular complex that regulates mitochondrial transport within neurons and neuronal death. The discovery of a complex present exclusively in the most advanced mammals could help find new therapeutic targets against neurodegenerative diseases such as Parkinson’s disease, neuromuscular pathologies or even certain types of tumors.

The work, carried out in animal models and cell cultures, is led by Professor Eduardo Soriano from the University of Barcelona, ​​UB Neuroscience Institute (UBneuro) and the Network Biomedical Research Center for Neurodegenerative Diseases (CIBERNED), and researcher Anna Maria Aragai, member of the Conseil Superior de la Recherche Scientifique (CSIC) and the Institute of Molecular Biology of Barcelona (IBMB-CSIC).

The article, whose first authors are Ismael Izquierdo (IBMB-CSIC), Serena Mirra and Yasmina Manso (UB-CIBERNED), also highlights the participation of Adolfo López de Munaín from the University Hospital of Donostia and Xavier Navarro from the Autonomous University. Barcelona (UAB), both members of the CIBERNED group, and José Antonio Henriques, a member of the Center for Biomedical Research on Frailty and Healthy Aging (CIBERFES) and the Carlos III National Center for Cardiovascular Research (CNIC).

Provide energy for neuronal functions

“In neurons, the process of mitochondrial transport is critical because these organelles must be present along all axons and dendrites—the processes of neurons—to provide energy for neurotransmission and neuronal function, processes with large energy demands. This large consumption depends on the very specific and precise distribution of mitochondria within neurons,” explains Soriano, co-principal investigator of the study and a member of the Department of Cell Biology, Physiology and Immunology in the Faculty of Biology at UB.

The study shows that the mitochondrial Alex3/Gαq complex interacts with the mitochondrial machinery to distribute and transport these cellular organelles across neuronal axons and dendrites. This entire transport process depends on the interaction of the Gq protein with the mitochondrial protein Alex3.

“For the first time, we discovered that the Alex3/Gαq complex is important not only for mitochondrial transport and function, but also for neuronal physiology, motor control and neuronal viability. If this system is inactivated—for example, in mice with a specific deficiency of the Alex3 protein in the central nervous system—mitochondrial traffic is reduced, less dendritic and axonal branching occurs, and this causes motor deficits and even neuronal death.” Details Aragay, co-leader of the investigation.

The authors of the work have previously described in previous articles that the Alex3 and Gαq proteins regulate mitochondrial transport. However, until now it was unknown how they interact and what molecular mechanisms are involved in this process.

The interaction of the mitochondrial Alex3/Gαq complex is regulated through G protein-coupled receptors. (G protein coupled receptors, GPCR), as the work showed. These are receptors for many molecules—hormones, neurotransmitters, cannabinoids, etc.—that perform different functions in the body.

“Activation of GPCRs not only changes the distribution of mitochondria, but also their function and, most notably, the growth and viability of neurons. Our study suggests that, overall, these molecules that interact with these receptors may regulate various aspects of mitochondrial biology through GPCRs,” the experts elaborate.

Controlling receptors to fight human diseases

Although the mechanisms of action are still not well understood, it appears that the different functions performed by the Alex3 protein may be associated with various pathologies. For example, everything indicates that deletions (loss of a DNA fragment) of a gene Alex3 They contribute to the appearance of certain tumors (epithelial cancer). In other cases, deletion or inhibition of its expression has a protective effect in certain tumors (liver cancer).

In addition to being linked to cancer, some genetic variants of the Alex3 protein and its gene families are also associated with neurodegenerative diseases, particularly Parkinson’s disease, sleep apnea and metabolic diseases.

“The fact that no inactivating mutations have been identified in databases of thousands of human genomes indicates that the gene Alex3 It has a very relevant function. Its complete loss is not viable in the body and can only be detected as a somatic mutation in tumors,” says Professor Gemma Marfani, co-author of the paper and member of UU’s Department of Genetics, Microbiology and Statistics. UB Institute of Biomedicine (IBB) and Networked Biomedical Research Center for Rare Diseases (CIBERER).

“In addition, mutations in the gene encoding Gαq in humans lead to movement disorders, cognitive deficits, mental retardation and epilepsy,” says Aragay. The authors emphasize that these data show the significance of the identified complex for neuronal function.

“The ability to control mitochondrial biology from outside cells through GPCR receptors is a big advantage. Currently, there are many specific molecules that activate or inhibit these receptors, so it is important to explore the possibility of controlling the localization and biology of mitochondria in diseases in which there is a deficiency of these organelles (for example, mitochondrial or neuromuscular diseases). ), or in pathologies where inhibition of metabolism has a beneficial therapeutic effect (for example, cancer),” the team concludes.

Help Article:

Izquierdo Villalba, I.; Mirra, S. et al. “The Mammalian-Specific Alex3/Gαq Protein Complex Regulates Mitochondrial Transport, Dendritic Complexity, and Neuronal Survival.” Scientific alarmFebruary 2024. DOI: 10.1126/scisignal.abq1007.

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