Heat shock protein expression in cerebral X‐linked adrenoleukodystrophy reveals astrocyte stress prior to myelin loss. (26th April 2017)

• Record Type: Journal Article
• Authors: Görtz, A. L.; Peferoen, L. A. N.; Gerritsen, W. H.; van Noort, J. M.; Bugiani, M.; Amor, S.
• Is Part Of: Neuropathology & applied neurobiology. Volume 44:Number 4(2018)
• Page Start: 363
• Page End: 376
• Publication Date: 2017-04-26
• Subjects: astrocytes -- central nervous system -- demyelination -- heat shock proteins -- HSP -- inflammation -- X‐ALD -- X‐linked adrenoleukodystrophy; Nervous system -- Diseases -- Pathology -- Periodicals; Nervous system -- Diseases -- Periodicals; 616.8
• DOI: 10.1111/nan.12399
• Languages: English
• ISSNs: 0305-1846

Abstract

Abstract : 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.