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Heat shock protein expression in cerebral X‐linked adrenoleukodystrophy reveals astrocyte stress prior to myelin loss
Author(s) -
Görtz A. L.,
Peferoen L. A. N.,
Gerritsen W. H.,
Noort J. M.,
Bugiani M.,
Amor S.
Publication year - 2018
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1111/nan.12399
Subject(s) - inflammation , myelin , heat shock protein , white matter , pathogenesis , multiple sclerosis , pathology , microglia , adrenoleukodystrophy , downregulation and upregulation , astrocyte , biology , oligodendrocyte , immunology , medicine , neuroscience , gene , central nervous system , genetics , peroxisome , magnetic resonance imaging , radiology
Aims X‐linked adrenoleukodystrophy (X‐ALD) is a genetic white matter disorder in which demyelination occurs due to accumulation of very long‐chain fatty acids. Inflammation in the brain white matter is a hallmark of the pathology of cerebral X‐ALD, but the underlying pathogenic mechanisms are still largely unknown. In other inflammatory demyelinating disorders, such as multiple sclerosis, the expression of heat shock proteins (HSPs) in combination with interferon‐γ (IFN‐γ) has been suggested to play a prominent role in the initiation of demyelination and inflammation. We therefore investigated these pathways in X‐ALD lesions. Methods By immunohistochemistry, we examined the expression of small HSPs (HSPB1, HSPB5, HSPB6, HSPB8) and higher molecular weight HSPs (HSPA, HSPD1), and the expression of elements of the IFN‐γ pathway on autopsy material of five patients with X‐ALD. Results The expression of the larger HSPs, HSPA and HSPD1, as well as small HSPs is increased in X‐ALD lesions compared with normal‐appearing white matter. Such upregulation can already be detected before demyelination and inflammation occur, and it is predominant in astrocytes. The IFN‐γ pathway does not seem to play a leading role in the observed inflammation. Conclusions The finding that astrocytes show signs of cellular stress before demyelination suggests that they play a major role early in the pathogenesis of cerebral X‐ALD, and may therefore be involved in the initiation of inflammation and demyelination.