Apoptosis in the central nervous system of cerebral adrenoleukodystrophy patients

The childhood cerebral form of adrenoleukodystrophy (ALD) is a fatal demyel inating disease, yet mice deficient in the ALD gene do not show such clinic opathological phenotype. We have therefore investigated in human autopsy ti ssues whether the ALD gene mutation results in apoptosis of CNS cells. Spec imens from telencephalic and brainstem regions of four patients, and three controls were examined for internucleosomal DNA fragmentation, in situ dete ction of DNA breaks by the TUNEL method, and caspase-3 immunostaining. None of the controls showed significant apoptosis in white matter, while apopto tic nuclei with chromatin alterations were detected in areas of active demy elination in three ALD patients. A large proportion of apoptotic cells were oligodendrocytes and some express activated caspase-3. TUNEL-positive nucl ei and/or caspase-3 staining were also detected in perivascular infiltrates and, occasionally, in neurons. We conclude that apoptosis of oligodendrocy tes may account, at least in part, for the demyelinating process in the ALD brain. (C) 2000 Academic Press.