Dr. Quintana leads the Mitochondrial Neuropathology research group and laboratory (Quintanalab):
Group members:
Irene Bolea
Alex Gella
Pablo Machuca
Fabien Menardy
Kelsey Montgomery
Patricia Prada
Elisenda Sanz
Andrea Urpí
Former members:
Jessica Hui
Benjamin Bauer
RESEARCH INTERESTS
Mitochondria are the powerhouses of the cell. Mutations that render mitochondria unable to generate energy cause a group of rare and usually fatal pathologies collectively known as mitochondrial disease. It has been estimated that 1 in 5000 children will develop a mitochondrial disease. Currently, there is no cure for mitochondrial disease and the treatments available are mostly ineffective. Energy-demanding cells such as neurons are especially sensitive to mitochondrial disease, and they account for most of the clinical signs and symptoms observed in humans, such as hypotonia, ataxia, seizures and early death.However, even if every single cell in the body carries the mutation, only specific brain areas seem to be affected by the deficiency. Our lab investigates the molecular mechanisms defining why some neuronal populations are particularly affected by mitochondrial disease, with the overarching goal of identifying novel targets that lead to improved treatments for mitochondrial disease patients.
CURRENT WORK
The Quintana lab current research focuses on identifying the neuronal populations susceptible to mitochondrial disease and which mechanisms are making these neurons die. This knowledge is essential to understand and fight these incurable diseases. The Quintana lab uses a wide array of approaches, combining molecular biology, stereotaxic surgery, mouse genetics and behavior, biochemistry, histology, optogenetics and in vivo electrophysiology to reveal novel pathways and mechanisms in neuronal function and pathology and open new and unexplored lines of research and therapeutic targets to treat mitochondrial disease encephalopathy.
STRATEGIC OBJECTIVES
Mitochondria generate most of the energy that cells require to function properly. Dysfunctions in the mitochondrial energy-producing machinery causes a group of severe and progressive pathologies collectively named mitochondrial disease. 1 in 5000 births will be affected by mitochondrial disease, severely and progressively impairing the normal development of the child. Although the disease is usually fatal, there is no cure, or even effective treatments for mitochondrial disease.
The central nervous system, and neurons in particular, are high energy-requiring tissues and cells. Hence, they are severely affected in mitochondrial disease and alterations in their functioning cause most of the clinical signs and symptoms observed in patients and that ultimately lead to premature death. However, even though usually all neuronal populations present the same mutation only discrete neuronal groups are affected and die. Our research focuses on identifying the cellular mechanisms that underlie this susceptibility to mitochondrial alterations. Our studies combine histological, molecular, electrophysiological, optegenetic and behavioral approaches to identify new neural circuits and mechanisms involved in neuronal function and mitochondrial pathology with the overarching goal to generate new therapeutic targets.
MAIN RESEARCH LINES
1) Identifying the molecular changes in susceptible neuronal populations.
The cellular mechanisms underlying whether a neuron dies or survives mitochondrial alterations are not clear. Our results using an animal model of mitochondrial disease have identified the neuronal populations that are affected the most. We hypothesize that transcriptional and translational changes are underlying the neuronal fate of a neuron with mitochondrial alterations. Given the high anatomical and cellular specificity of mitochondrial disease and the heterogeneity of the neural tissue new technologies are required to be able to observe such changes in affected neurons. Our lab is developing new methods to identify these changes with a cell-specific resolution. This will allow the characterization of the mechanisms and cellular pathways involved in the mitochondrial pathologies and identify new potential therapies.
2) Establishing the functional connectome of the vestibular nucleus.
Our studies have identified the vestibular nucleus, in the brainstem, as a key player in the physiological and behavioral changes observed in mice with mitochondrial deficits. The vestibular nucleus is divided in different regions that connect extensively with other brain areas. Even though it is involved in many different functions such as the control of balance, blood pressure or breathing the circuitry underlying all these functions has not been elucidated. Our lab uses stereotaxic surgery and in vivo electrophysiological approaches to identify the vestibular projections involved in these physiological responses and the role they play in mitochondrial disease.
3) Identify new therapeutic targets to mitochondrial encephalopathy.
Our results have identified two signaling cascades that are altered in mice with mitochondrial dysfunction: mTOR and SREBP/JNK. Our lab has characterized that blocking mTOR extends lifespan of affected mice 5-fold and that the administration of antioxidants ameliorates the disease progression and delays the clinical features of the disease. Building upon this, our current studies are focused on characterizing and identifying the downstream factors involved in these positive effects to further our knowledge and to identify new treatments for mitochondrial disease.
COLLABORATIONS
- Dr. Richard Palmiter, Howard Hughes Medical Institute and University of Washington, USA
- Dr. Nino Ramirez, Seattle Children’s Research Institute, USA
- Dr. Phil Morgan, Seattle Children’s Research Institute, USA
- Dr. Margaret Sedensky, Seattle Children’s Research Institute, USA
- Dr. Hugo Bellen, Howard Hughes Medical Institute and Baylor College of Medicine, USA.
- Dr. Francois H. van der Westhuizen, North-West University, South Africa
- Dr. Iain L Campbell, University of Sydney, Australia
