Fundamental and pathophysiological mechanisms implicated in ataxia
Hereditary ataxias are a heterogeneous set of severely disabling neurological disorders caused by degeneration of the cerebellum and/or the spinal cord. The prevalence of hereditary ataxias is estimated to 1/20,000 individuals in Europe, and yet there are no specific treatments for most of them.
Our research focuses on understanding the pathophysiology of ataxia, discovering disease biomarkers and developing therapeutic approaches. In addition, in close collaboration with the clinicians, we are developing new diagnostics tools for cerebellar ataxia and identify novel genes causing ataxia.
We are mainly interested in two different recessive ataxias, Friedreich ataxia (FA) and autosomal recessive cerebellar ataxia 2 (ARCA2), linked to two essential mitochondrial pathways: iron-sulfur cluster (ICS) biosynthesis and coenzyme Q10 (CoQ10) biosynthesis, respectively; FA belongs to the family of trinucleotide repeat disorders, which are caused by dynamic mutations that show instability (expansion/contraction) in the germline and in selective somatic cells.
Friedreich ataxia (FA), the most common recessive ataxia, is characterized by progressive gait and limb ataxia associated with hypertrophic cardiomyopathy and an increase incidence in diabetes. The major mutation is a GAA repeat expansion within the first intron of the FXN gene. In FA, the GAA expansion leads to heterochromatinization of the locus resulting in a drastic decrease of transcription of FXN. The disease results from loss of function of FXN gene product, frataxin, a highly conserved mitochondrial protein involved in the biogenesis of ISC, which are essential protein cofactors implicated in numerous cellular functions.
The autosomal recessive cerebellar ataxia 2 (ARCA2) is characterized by cerebellar ataxia and atrophy, and is associated with exercise intolerance. Most patients present a mild deficiency in CoQ10 in muscle biopsies. ARCA2 results from mutations in the ADCK3/COQ8A gene that encodes a mitochondrial protein with a regulatory role in CoQ10 biosynthesis.
Understanding how a dynamic regulation of cellular energy contributes to the development of neuronal circuits.
PROJECTS
Our group focuses on some of the fundamental mechanisms underlying the development of neuronal circuits in the cerebral cortex. Neurons are among the most polarized cells in the organism. The axon typically exceeds the length of the cell body by several orders of magnitude. This extreme morphology raises many cellular challenges: in particular, the delay required to transport organelles and cargo from the soma to distant parts of the axon can reach several hours and is incompatible with the rapid adaptation of subcellular homeostasis. Thus, size constraints suggest that distinct regions of the axon behave as de facto isolated subcellular compartments, and that neurons have evolved strategies to ensure tight spatial and temporal control of critical cellular functions. Understanding the molecular connections between the local regulation of subcellular homeostasis and axon morphogenesis is therefore a critical challenge in cellular neurobiology.
To address this question, our research concentrates on the local regulation of the energy metabolism in the developing axon. Indeed, the rapid remodeling of the axon during local morphogenetic events such as axon elongation, branch formation and elimination and synapse consolidation has an important energetic toll. Our goal is to characterize some of the molecular and cellular mechanisms involved in the local regulation of the energy metabolism in the axon during the embryonic and postnatal development, and to understand the consequences of disrupting the energy metabolism of developing neurons on axon development and circuit formation in the mouse. Our research combines real-time measurement of metabolic activity in developing neurons and in vivo manipulation of gene expression to determine the role of signaling pathways on mitochondria function, cortical axon development and mouse behavior.