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The Journal of Neuroscience, February 25, 2004, 24(8):1987-1995; doi:10.1523/JNEUROSCI.4549-03.2004

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Neurobiology of Disease
Friedreich Ataxia Mouse Models with Progressive Cerebellar and Sensory Ataxia Reveal Autophagic Neurodegeneration in Dorsal Root Ganglia

Delphine Simon,¹ Hervé Seznec,¹ Anne Gansmuller,¹ Nadège Carelle,¹ Philipp Weber,¹ Daniel Metzger,¹ Pierre Rustin,² Michel Koenig,¹ and Hélène Puccio¹

¹Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale (INSERM)/Université Louis Pasteur, 67404 Illkirch cedex, CU de Strasbourg, France, and ²Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U393, Hôpital Necker-Enfants Malades, 75015 Paris, France

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.

Key words: behavior; degeneration; dorsal root ganglion; DRG; mitochondria; neuropathology; Purkinje cell; mouse model; Friedreich ataxia

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Received Oct 7, 2003; revised November 28, 2003; accepted January 1, 2004.

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