New article!

We have a new article! Elife published our study in Leigh Syndrome, the most common mitochondrial disease with affectation of the central nervous System. In this disease, there are two brain regions that are particularly compromised: the brainstem (that controls all basic functions that keep us alive) and the basal ganglia, involved in refining motor coordination. In our study, we wanted to explore the role the protein Ndufs4 has in this affectation.

Ndufs4 is a subunit of the Complex I. It is located in the mitochondrial membrane and is involved in the respiratory chain. We knew that animal models lacking this subunit in all their cells reproduce the classical signs of Leigh Syndrome, but 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 the gene codifying the protein Ndufs4 in three neuronal populations we suspected could be key, and keep it working in all other cells in the body. Observing what symptoms remained we could know the role of these neurons in the 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.

These results are very important to contribute understand the underlying cellular mechanisms of Leigh Syndrome, as we identified which specific neurons are behind the brain alterations. 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.

Congrats to all the team and collaborators!

The wheels are running!

Wow! what a busy time this past year has been!

Many (good) things and (good) news to explain! New members, new papers, exciting science… here you are a picture of the lab just before summer break!

quintanalab 2017

First of all, we are glad to announce three! new additions to the lab: Kelsey, Fabien and Patrizia. (disclaimer: they have already been with us for some months, but hey, I told you we have been really busy!)

Kelsey Montgomery has re-joined the lab as a part-time research technician/MSc student (Bioinformatics). She graduated (BSc. Genetics) from the University of Georgia (2013) and worked at Seattle Genetics (2013-2015) before joining the Quintana lab in Seattle (2015). We are excited to have her with us again on the other side of the pond!

Fabien Menardy (aka Fab) has joined the lab as a postdoctoral fellow and is our resident optogenetics/in vivo electrophysiology expert. Fabien graduated (PhD Neurosciences) from the University of Paris Sud (2012) under the supervision of Dr. Catherine del Negro, where he worked on elucidating neural responses involved in zebra finch vocal communication signaling. After obtaining his PhD, he joined the lab of Dr. Daniela Popa and Dr. Clément Lena, at the École Normal Supérieure, Institut de Biologie (Paris), as a postdoctoral researcher (2013-2016) where he focused on understanding the role of the cerebellum in Parkinson’s Disease. He is now interested in understanding the electrophysiological alterations (and their implications in circuit signal processing) in neurons with mitochondrial dysfunction. 

Patrizia Bianchi joined the lab as a postdoctoral fellow and is an expert in mitochondrial dynamics. Patrizia graduated (PhD Biomedicine) from the Universitat de Barcelona (2016) under the supervision of Dr. Aurora Pujol (IDIBELL), where she worked on elucidated the alterations in mitochondrial dynamics in X-linked adrenoleukodystrophy. She is now focusing on characterizing the underlying deficits in mitochondrial dynamics in animal models of Leigh Syndrome.

We are glad to have such talented scientists in the lab!

Last, but not least, and even though there will be other posts providing brief summaries, we are glad to have had two articles recently accepted! Hooray!

Here you are the links, for those interested:

Striatal GPR88 modulates foraging efficiency (Journal of Neuroscience)

Loss of mitochondrial Ndufs4 in striatal medium spiny neurons mediates progressive motor impairment in a mouse model of Leigh Syndrome (Frontiers in Molecular Neuroscience). OPEN ACCESS

Will keep you updated!!

 

Research: Altered protein modifications in mitochondrial disease

Our latest paper is out!

In collaboration with the Frizzell lab at the University of South Carolina we have published the article titled:

Succination is increased on select proteins in the brainstem of the Ndufs4 knockout mouse, a model of Leigh syndrome.” 

in the journal Molecular and Cellular Proteomics.

In this paper, we have been able to identify that the metabolic deficits mediated by mitochondrial dysfunction (we used our Leigh Syndrome mice for this study) lead to permanent modifications in discrete proteins in affected neurons.

These modifications (called succination) have been shown to impair the activity of proteins in other studies, therefore we believe these mitochondrial proteins will also lose function in our model. Interestingly, our study shows that these modifications are only observed in cells residing in areas affected by the pathology, further enhancing the idea that they may mediate the selective damage observed in mitochondrial disease.

The main proteins observed to be altered, VDAC1 and VDAC2, are key factors controlling transport of ions and molecules inside the mitochondria, so these results open a new and interesting line of research in the lab in the overarching goal of finding a cure for mito disease.

 

 

 

Our latest paper is out!

We are really excited that our latest paper, in collaboration with the Bellen lab at Baylor, has been published in the prestigious journal Cell.

Our work, titled: Glial lipid droplets and ROS induced by mitochondrial defects promote neurodegeneration, has identified a conserved mechanism that leads to neuronal death after mitochondrial defects.

In this study, the Bellen lab, using the fruit fly as a model, identified that mitochondrial mutations causing reactive oxygen species (aka oxidative stress) induced  the accumulation of lipid droplets in glia, the cells that surround and support neurons, via activation of a pathway known as JNK/SREBP. Lipid droplets are energy storage organelles, especially when neurons are faulty, but when these lipid droplets become peroxidated glia is unable to support neurons, leading to their demise.

graphical abstract final

Credit: CellPress (cell.com)

Our work was key in identifying that this mechanism was present in mice, suggesting it has been evolutionary conserved, highlighting its potential importance.

Finally, we used a potent antioxidant, AD4, that crosses the blood-brain-barrier (which limits the access of many drugs to the brain), and showed that it was able to reduce and delay the onset of the disease.

We are really excited of the future therapeutic potential of this approach and we are really happy of this fruitful collaboration (pun intended!).

The article can be accessed here.