Heat shock protein expression in cerebral X-linked adrenoleukodystrophy reveals astrocyte stress prior to myelin loss.
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.
['Görtz|A L|AL|0000-0002-4455-1432', 'Peferoen|L A N|LAN|', 'Gerritsen|W H|WH|', 'van Noort|J M|JM|', 'Bugiani|M|M|', 'Amor|S|S|']
D000293:Adolescent D000326:Adrenoleukodystrophy D000328:Adult D001253:Astrocytes D002540:Cerebral Cortex D002648:Child D003711:Demyelinating Diseases D006360:Heat-Shock Proteins D006801:Humans D008297:Male D008875:Middle Aged D009186:Myelin Sheath D066127:White Matter
heat shock proteins X-linked adrenoleukodystrophy astrocytes X-ALD demyelination inflammation HSP central nervous system