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Publications of the Week

Defined Neuronal Populations Drive Fatal Phenotype in a Mouse Model of Leigh Syndrome

By August 30, 2019No Comments

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This week we profile a recent publication in eLife from Irene Bolea in the laboratory of Albert Quintana (pictured, back),
previously at the Seattle Children’s Research Institute and currently at the Universitat Autònoma de Barcelona.

Can you provide a brief overview of your lab’s current research focus?

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. 1 in 5000 children in the US 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.

The Quintana lab’s 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, ranging from molecular biology, optogenetics and electrophysiology, to mouse genetics and behavior, to reveal novel pathways and mechanisms in neuronal function and pathology and to open new and unexplored lines of research and therapeutic targets to treat mitochondrial disease encephalopathy.

What is the significance of the findings in this publication?

In this work, we have studied different new mouse models that have mitochondrial dysfunction only in specific groups of neurons, namely glutamatergic (“go” neurons), GABAergic (“stop” neurons) and cholinergic neurons (important to convey information from the brain to the organs). Using a combination of molecular, genetic, and physiological approaches, we have identified that glutamatergic and GABAergic neurons are the ones involved in the progression of the disease. In particular, glutamatergic neurons in the brainstem are responsible for the motor and respiratory alterations, while GABAergic neurons in the basal ganglia lead to severe epilepsy.

What are the next steps for this research?

Our study has provided novel tools for researchers and has identified the neurons involved in the disease. These new tools could help researchers to identify the specific cellular mechanisms that cause a neuron to die, or survive, when facing faulty mitochondria. This knowledge is the stepping stone to develop effective treatments for mitochondrial disease.

This work was funded by:

Northwest Mitochondrial Research Guild 
Seattle Children’s Research Institute Seed Funds
European Research Council (ERC)
Ministerio de Economia y Competitividad (Spain)
AGAUR (Catalonia)

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