We published our first preprint last week. For those who aren’t familiarized, a preprint is a study to be published in a Journal, that has not been reviewed yet. The aim is to make the results available as soon as possible so Science can advance faster. We are very excited about it, and very happy because it has been featured by the preprint platform Biorxiv for reaching the top 5% altmetric score within their first days after releasing it; and it has also been selected as one of the ERC Research results of the week! So cool!
But what is it about?
As you may know, dysfunctions of the mitochondrial energy-generating machinery cause a series of usually fatal diseases collectively known as mitochondrial disease. In this disease, high energy-requiring organs, like the brain, are especially affected, showing many severe symptoms such as motor alterations, respiratory deficits or epilepsy that, in many cases, can be fatal. Hence, our group is driven to better understand these pathologies, with the overarching goal of finding effective therapies to treat them.
This time, we focused on Leigh Syndrome, the most common presentation of mitochondrial disease with a predominant affectation of the central nervous system, particularly in two brain areas, the brainstem (that controls all basic functions that keep us alive) and the basal ganglia, involved in refining motor coordination. We knew that one protein in the mitochondria is critical in this disease: the Complex I subunit NDUFS4, because animal models lacking this subunit in all their cells reproduce the classical signs of Leigh Syndrome described before. However, there were some pressing questions remaining: do symptoms appear due to all cells in the body not working properly, or some specific cells are responsible for them?
To study this, we selectively inactivate NDUFS4 in three neuronal populations we suspected could be key, and keep NDUFS4 working in all other cells in the body. Observing what symptoms remained we could know the role of these neurons in the brain alterations these patients suffer.
What we found was that the inactivation of this subunit in a certain kind of excitatory neurons (the fancy-scientist name is vlgut2-expression glutamatergic neurons) caused brainstem inflammation, motor and respiratory deficits, and early death; and that its inactivation in inhibitory (GABAergic neurons) led to basal ganglia inflammation, severe refractory epileptic seizures and premature death.
Bottom line, these results are very important to contribute understand the underlying cellular mechanisms of mitochondrial disease in general, and Leigh Syndrome in particular, as we have identified which specific neurons are behind the brain lesions observed in this pathology and their specific contribution to the symptoms. Therefore, now we have new knowledge to try to identify which cellular aspects are failing in those cells so we can start to envisage different methods to correct them.