Human Molecular Genetics Advance Access originally published online on October 13, 2005
Human Molecular Genetics 2005 14(23):3565-3577; doi:10.1093/hmg/ddi384
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Inactivation of the peroxisomal ABCD2 transporter in the mouse leads to late-onset ataxia involving mitochondria, Golgi and endoplasmic reticulum damage
1Institut 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, 2Anatomisches Institut, Universität Basel, Pestalozzistr. 20, CH-4056 Basel, Switzerland, 3Institut 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, 4Laboratory of Genetic Metabolic Diseases, Department of Clinical Chemistry and Department of Pediatrics, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, PO Box 22700, 1100 DE Amsterdam, The Netherlands, 5Stem Cell Research Institute, DIBIT, San Raffaele Science Park, Via Olgettina 58, Milan, Italy, 6Societé Neurofit, SA 67404 Illkirch Cedex, C.U. de Strasbourg, France and 7Istitució Catalana de Recerca i Estudis Aplicats (ICREA) and Centre de Genètica Mèdica i Molecular, IRO/IDIBELL, Gran Via s/n, km 2.7, 08907 L'Hospitalet de Llobregat, Barcelona, Spain
* To whom correspondence should be addressed at: CGMM, IRO/IDIBELL, Hospital Duran i Reynals, Gran Via s/n, km 2.7, 08907 L'Hospitalet de Llobregat, Barcelona, Spain. Tel: +34 932607425; Fax: +34 932607414; Email: apujol{at}iro.es
Received July 12, 2005; Accepted October 6, 2005
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 four ABC transporters (ABCD1 to ABCD4) has been related to fatty acid transport, because patients with mutations in ABCD1 (ALD gene) suffer from X-linked adrenoleukodystrophy (X-ALD), a disease characterized by an accumulation of very-long-chain fatty acids (VLCFAs). Inactivation in the mouse of the abcd1 gene leads to a late-onset neurodegenerative condition, comparable to the late-onset form of X-ALD [Pujol, A., Hindelang, C., Callizot, N., Bartsch, U., Schachner, M. and Mandel, J.L. (2002) Late onset neurological phenotype of the X-ALD gene inactivation in mice: a mouse model for adrenomyeloneuropathy. Hum. Mol. Genet., 11, 499–505.]. In the present work, we have generated and characterized a mouse deficient for abcd2, the closest paralog to abcd1. The main pathological feature in abcd2–/– mice is a late-onset cerebellar and sensory ataxia, with loss of cerebellar Purkinje cells and dorsal root ganglia cell degeneration, correlating with accumulation of VLCFAs in the latter cellular population. Axonal degeneration was present in dorsal and ventral columns in spinal cord. We have identified mitochondrial, Golgi and endoplasmic reticulum damage as the underlying pathological mechanism, thus providing evidence of a disturbed organelle cross-talk, which may be at the origin of the pathological cascade.
Present address: Phytopharm PLC, Cambridge, England.
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