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

[adrenomyeloneuropathy]

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 (ABCD 1 to ABCD 4 ) has been related to fatty acid transport , because patients with mutations in ABCD 1 (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 abcd 1 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 abcd 2 , the closest paralog to abcd 1 . The main pathological feature in abcd 2 -/- 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 .

Diseases
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Diseases presenting "accumulation of vlcfas in the latter cellular population" symptom

adrenomyeloneuropathy

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