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01-12-2007 | Original Paper

Lack of adrenoleukodystrophy protein enhances oligodendrocyte disturbance and microglia activation in mice with combined Abcd1/Mag deficiency

Authors: Martina Dumser, Jan Bauer, Hans Lassmann, Johannes Berger, Sonja Forss-Petter

Published in: Acta Neuropathologica | Issue 6/2007

Abstract

X-linked adrenoleukodystrophy (X-ALD) is an inherited neurometabolic disease associated with the accumulation of very long-chain 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. ALDP-deficient mice replicate metabolic dysfunctions and develop late-onset 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 X-ALD and the mild myelin abnormalities of myelin-associated glycoprotein (MAG) deficiency. A behavioural phenotype, impaired motor performance and tremor, developed in middle-aged 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 double-knockout (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 double-ko 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 Abcd1-deficient mice, implying that oligodendrocyte/myelin disturbances may precede axonopathy in X-ALD.

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Title: Lack of adrenoleukodystrophy protein enhances oligodendrocyte disturbance and microglia activation in mice with combined Abcd1/Mag deficiency
Authors: Martina Dumser
Jan Bauer
Hans Lassmann
Johannes Berger
Sonja Forss-Petter
Publication date: 01-12-2007
Publisher: Springer-Verlag
Published in: Acta Neuropathologica / Issue 6/2007
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-007-0288-4

At a glance: The STEP trials

Springer Medicine

Lack of adrenoleukodystrophy protein enhances oligodendrocyte disturbance and microglia activation in mice with combined Abcd1/Mag deficiency

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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