Inactivation of the peroxisomal ABCD2 transporter in the mouse leads to late-onset ataxia involving mitochondria, Golgi and endoplasmic reticulum damage

• Published in: Human molecular genetics 2005-12, Vol.14 (23), p.3565-3577
• Main Authors: Ferrer, Isidre, Kapfhammer, Josef P., Hindelang, Colette, Kemp, Stephan, Troffer-Charlier, Nathalie, Broccoli, Vania, Callyzot, Noëlle, Mooyer, Petra, Selhorst, Jacqueline, Vreken, Peter, Wanders, Ronald J.A., Mandel, Jean Louis, Pujol, Aurora
• Format: Article
• Language: English
• Subjects: Animals; ATP Binding Cassette Transporter, Sub-Family D; ATP-Binding Cassette Transporters; ATP-Binding Cassette Transporters - genetics; Behavior, Animal; Biochemistry, Molecular Biology; Biological and medical sciences; Cerebellum; Cerebellum - pathology; Disease Models, Animal; Endoplasmic Reticulum; Endoplasmic Reticulum - pathology; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Golgi Apparatus; Golgi Apparatus - pathology; Life Sciences; Medical sciences; Mice; Mice, Knockout; Mitochondria; Mitochondria - pathology; Molecular and cellular biology; Molecular biology; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Spinal Cord; Spinal Cord - pathology; Spinal Cord - physiopathology; Spinocerebellar Degenerations; Spinocerebellar Degenerations - genetics; Spinocerebellar Degenerations - pathology; Spinocerebellar Degenerations - physiopathology
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddi384

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.