Fiche publication
Date publication
février 2004
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Auteurs
Membres identifiés du Cancéropôle Est :
Dr METZGER Daniel
Tous les auteurs :
Simon D, Seznec H, Gansmuller A, Carelle N, Weber P, Metzger D, Rustin P, Koenig M, Puccio H
Lien Pubmed
Résumé
Friedreich ataxia (FRDA), the most common recessive ataxia, is characterized by degeneration of the large sensory neurons of the spinal cord and cardiomyopathy. It is caused by severely reduced levels of frataxin, a mitochondrial protein involved in iron-sulfur cluster (ISC) biosynthesis. Through a spatiotemporally controlled conditional gene-targeting approach, we have generated two mouse models for FRDA that specifically develop progressive mixed cerebellar and sensory ataxia, the most prominent neurological features of FRDA. Histological studies showed both spinal cord and dorsal root ganglia (DRG) anomalies with absence of motor neuropathy, a hallmark of the human disease. In addition, one line revealed a cerebellar granule cell loss, whereas both lines had Purkinje cell arborization defects. These lines represent the first FRDA models with a slowly progressive neurological degeneration. We identified an autophagic process as the causative pathological mechanism in the DRG, leading to removal of mitochondrial debris and apparition of lipofuscin deposits. These mice therefore represent excellent models for FRDA to unravel the pathological cascade and to test compounds that interfere with the degenerative process.
Mots clés
Animals, Ataxia, etiology, Autophagy, genetics, Cerebellar Ataxia, etiology, Disease Models, Animal, Disease Progression, Friedreich Ataxia, complications, Ganglia, Spinal, pathology, Iron-Binding Proteins, genetics, Mice, Mice, Knockout, Mice, Neurologic Mutants, Motor Activity, Nerve Degeneration, genetics, Phenotype, Sensation Disorders, genetics
Référence
J. Neurosci.. 2004 Feb;24(8):1987-95
