PT  - JOURNAL ARTICLE
AU  - Delphine Simon
AU  - Hervé Seznec
AU  - Anne Gansmuller
AU  - Nadège Carelle
AU  - Philipp Weber
AU  - Daniel Metzger
AU  - Pierre Rustin
AU  - Michel Koenig
AU  - Hélène Puccio
TI  - Friedreich Ataxia Mouse Models with Progressive Cerebellar and Sensory Ataxia Reveal Autophagic Neurodegeneration in Dorsal Root Ganglia
AID  - 10.1523/JNEUROSCI.4549-03.2004
DP  - 2004 Feb 25
TA  - The Journal of Neuroscience
PG  - 1987--1995
VI  - 24
IP  - 8
4099  - http://www.jneurosci.org/content/24/8/1987.short
4100  - http://www.jneurosci.org/content/24/8/1987.full
SO  - J. Neurosci.2004 Feb 25; 24
AB  - 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.