Lack of adrenoleukodystrophy protein enhances olig

Authors: Martina Dumser Jan Bauer Hans Lassmann Johannes Berger Sonja ForssPetter

Publish Date: 2007/09/09

Volume: 114, Issue: 6, Pages: 573-586

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Abstract

Xlinked adrenoleukodystrophy XALD is an inherited neurometabolic disease associated with the accumulation of very longchain fatty acids Mutations in the ABCD1 gene encoding ALD protein ALDP cause this clinically heterogeneous disorder ranging from adrenocortical insufficiency and neurodegeneration to severe cerebral inflammation and demyelination ALDPdeficient mice replicate metabolic dysfunctions and develop lateonset axonopathy but lack histological signs of cerebral inflammation and demyelination To test the hypothesis that subtle destabilization of myelin may initiate inflammatory demyelination in Abcd1 deficiency we generated mice with the combined metabolic defect of XALD and the mild myelin abnormalities of myelinassociated glycoprotein MAG deficiency A behavioural phenotype impaired motor performance and tremor developed in middleaged Mag null mice independent of Abcd1 genotype Routine histology revealed no signs of inflammation or demyelination in the CNS but immunohistochemical analyses of spinal cord neuropathology revealed microglia activation and axonal degeneration in Mag and Abcd1/Mag doubleknockout ko and less severe and of later onset in Abcd1 mutants While combined Abcd1/Mag deficiency showed an additive effect on microglia activation axonal degeneration quantified by accumulation of amyloid precursor protein APP in axonal spheroids was not accelerated Interestingly abnormal APP reactivity was enhanced within compact myelin of Abcd1/Mag doubleko mice compared to single mutants already at 13 months These results suggest that ALDP deficiency enhances metabolic distress in oligodendrocytes that are compromised a priori by destabilised myelin Furthermore the age at which this occurs precedes by far the onset of axonal degeneration in Abcd1deficient mice implying that oligodendrocyte/myelin disturbances may precede axonopathy in XALDThe authors thank Drs KlausArmin Nave and Melitta Schachner for providing the Magdeficient mouse strain Ulrike Koeck Marianne Leisser Angela Kury and Martina Krammer for excellent technical assistance This work was supported by research grants from the European Association against Leukodystrophies ELA Nancy France the Myelin Project and the European Union project “XALD” LSHMCT2004502989

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