Heat shock protein expression in cerebral X-linked adrenoleukodystrophy reveals astrocyte stress prior to myelin loss.
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.



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.



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.



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.
Department of Pathology, VU University Medical Centre, Amsterdam, The Netherlands.
A L
0000-0002-4455-1432
AL
Görtz
Department of Pathology, VU University Medical Centre, Amsterdam, The Netherlands.
L A N
LAN
Peferoen
Department of Pathology, VU University Medical Centre, Amsterdam, The Netherlands.
W H
WH
Gerritsen
Delta Crystallon, Leiden, The Netherlands.
J M
JM
van Noort
Department of Pathology, VU University Medical Centre, Amsterdam, The Netherlands.|Department of Child Neurology, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands.
M
M
Bugiani
Department of Pathology, VU University Medical Centre, Amsterdam, The Netherlands.|Queen Mary University of London, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK.
S
S
Amor
D000293:Adolescent; D000326:Adrenoleukodystrophy / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D002648:Child; D003711:Demyelinating Diseases / Q000378:metabolism / Q000473:pathology; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology; D066127:White Matter / Q000378:metabolism / Q000473:pathology
D006360:Heat-Shock Proteins

HSP
; X-ALD; X-linked adrenoleukodystrophy; astrocytes; central nervous system; demyelination; heat shock proteins; inflammation