Human Molecular Genetics Advance Access published online on October 13, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi384
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1 Institut de Neuropatologia, Hospital Universitari de Bellvitge, Departament de Biologia Cel.lular i Anatomia Patologica, Facultat de Medicina, Universitat de Barcelona, IDIBELL c/ Feixa Llarga s/n E-08907 L'Hospitalet de Llobregat, Barcelona, Spain
* To whom correspondence should be addressed. ATP-binding cassette (ABC) transporters facilitate unidirectional translocation of chemically diverse substances, ranging from peptides to lipids, across cell or organelle membranes. In peroxisomes, a subfamily of 4 ABC transporters (ABCD1 to ABCD4) have been related to fatty acid transport, since patients with mutations in ABCD1 (ALD gene) suffer from X-linked adrenoleukodystrophy, a disease characterized by an accumulation of very long-chain fatty acids. Inactivation in the mouse of the abcd1 gene leads to a late-onset neurodegenerative condition, comparable to the late-onset form of X-ALD i.e adrenomyeloneuropathy (1). In the present work, we have generated and characterised a mouse deficient for abcd2, the closest paralog to abcd1. The main pathological features in abcd2-/- mice are a late-onset cerebellar and sensory ataxia, with loss of cerebellar Purkinje cells and dorsal root-ganglia cell degeneration, correlating with accumulation of very long-chain fatty acids in the latter cellular population. Axonal degeneration was present in dorsal and ventral columns in spinal cord. We have identified mitochondrial, Golgi and endoplasmatic reticulum damage as the underlying pathologic mechanism, thus providing evidence of a disturbed organelle cross-talk, which may be at the origin of the pathological cascade.
Received July 12, 2005
Revised October 6, 2005
Accepted October 6, 2005
Article
Inactivation of the peroxisomal ABCD2 transporter in the mouse leads to late-onset ataxia involving mitochondria, Golgi and endoplasmatic reticulum damage
2 Anatomisches Institut, Universität Basel, Pestalozzistr. 20, CH-4056 Basel, Switzerland
3 Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP and Collège de France, B.P.10142, 67404 Illkirch Cedex, C.U. de Strasbourg, France
4 Laboratory of Genetic Metabolic Diseases, Departments of Clinical Chemistry and Pediatrics, Emma Children's hospital, Academic Medical Center, University of Amsterdam, PO Box 22700, 1100 DE Amsterdam, The Netherlands
5 Stem Cell Research Institute, DIBIT, San Raffaele Science Park, Via Olgettina 58, Milan, Italy
6 Societé Neurofit, SA 67404 Illkirch Cedex, C. U. de Strasbourg, France
7 Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP and Collège de France, B.P.10142, 67404 Illkirch Cedex, C.U. de Strasbourg, France; Laboratory of Genetic Metabolic Diseases, Departments of Clinical Chemistry and Pediatrics, Emma Children's hospital, Academic Medical Center, University of Amsterdam, PO Box 22700, 1100 DE Amsterdam, The Netherlands
8 Centre de Genètica Mèdica i Molecular, IRO/IDIBELL, Hospital Duran i Reynals, Gran Via s/n, km 2.7, 08907 L'Hospitalet de Llobregat, Barcelona, Spain
Aurora Pujol, E-mail: apujol{at}iro.es
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