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Pathophysiology Of The Neurosensitive Involvement In Friedreich Ataxia Through The Generation And Characterisation Of New Cellular Models

Reference : PhD Hélène PUCCIO

Offer publication : April 6, 2016

Friedreich ataxia (FA) is the most frequent hereditary ataxia in Caucasians. FA is characterized by a progressive spinocerebellar and sensory ataxia. The first neurological symptoms generally appear around puberty and are often associated with non-neurological symptoms such as
cardiomyopathy. FA progressively evolves, and patients are confined to wheelchair around 10 to 15 years after onset. FA results from mutations in the FXN gene, which code for frataxin, a small mitochondrial protein. Frataxin is involved in the biogenesis of iron-sulfur clusters (Fe-S), small inorganic cofactors essential for cellular function.

The primary affected tissues include dorsal root ganglia (DRG), the spinal cord and the dentate nucleus of the cerebellum. Although several neurons are affected, data suggest that damages in the spinal cord result form trans-synaptic atrophy following the degeneration of DRG neurons. The implication of sensory neurons in the pathology is also illustrated by defects in the peripheral nervous system with loss of large myelinated fibers in the dorsal root whereas the size and myelin state of fibers in the ventral root remain unchanged.

Although affected structures are identified in FA, the mechanisms underlying neurodegeneration remains unknown. Some data were provided by the characterization of mouse models of the disease. In particular, the Prp28.6 mouse model that was generated in our lab reproduces the progressive
spinocerebellar and sensory ataxia. DRG are primarily affected in these mice due to the degeneration of large sensory neurons, a process that is characterized by the presence of autophagic vacuoles and defective mitochondria. Despite the capacity of the Prp mouse model to reproduce the phenotype, the analysis of the molecular and cellular mechanisms involved in the pathophysiology is difficult because affected cells are diluted in a complex and heterogeneous tissue. Approaches of molecular biology (western blot, qPCR) and biochemistry (enzymatic activities), which are classically used to assess Fe-S deficiency, mitochondrial defects or autophagy, cannot be used in this context.

Hence, to date, very few data exist on the neuronal pathophysiology of FA because no appropriate model of the disease is available to address these questions.

The goal of the thesis will be to generate new neuronal cellular models of FA from DRG of conditional mice. Two types of models will be generated in parallel: complete deletion of frataxin and partial loss of function of frataxin (through the expression of a frataxin bearing a missense mutation found in patients). These new models will provide sufficient material to study the pathophysiological mechanisms underlying the dysfunction of primary affected cells in FA, as well as the possibility to study cellular and molecular mechanisms that are difficult to tackle in vivo. In particular, the student will focus on the characterization of the mitochondrial dysfunction and on axonal mitochondrial transport through live imaging. This work will be completed by the
study of the mitochondrial phenotype in vivo, on a new mouse model recently generated in the lab, and in collaboration with Dr J. Magrane at the Cornell University of New York

- WISHED SKILLS : Motivated by research (bench work and bibliography), teamwork, and interest in human genetic and molecular and cellular biology

- EXPERTISES WHICH WILL BE ACQUIRED DURING THE TRAINING : This project will provide expertise in basic techniques of molecular and cellular biology (DNA, RNA, protein, cell culture); handling of AAV vectors for the transduction of primary culture cells; work with transgenic mice; photonic microscopy and live imaging.

Your application

Application Deadline : Dec. 31, 2016

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