Lack of X-linked inhibitor of apoptosis protein leads to increased apoptosis and tissue loss following neonatal brain injury.
Neurological deficits caused by H-I (hypoxia-ischaemia) to the perinatal brain are often severely debilitating and lead to motor impairment, intellectual disability and seizures. Perinatal brain injury is distinct from adult brain injury in that the developing brain is undergoing the normal process of neuronal elimination by apoptotic cell death and thus the apoptotic machinery is more easily engaged and activated in response to injury. Thus cell death in response to neonatal H-I brain injury is partially due to mitochondrial dysfunction and activation of the apoptosome and caspase 3. An important regulator of the apoptotic response following mitochondrial dysfunction is XIAP (X-linked inhibitor of apoptosis protein). XIAP inhibits apoptosis at the level of caspase 9 and caspase 3 activation, and lack of XIAP in vitro has been shown to lead to increased apoptotic cell death. In the present study we show that mice lacking the gene encoding the XIAP protein have an exacerbated response to neonatal H-I injury as measured by tissue loss at 7 days following the injury. In addition, when the XIAP-deficient mice were studied at 24 h post-H-I we found that the increase in injury correlates with an increased apoptotic response in the XIAP-deficient mice and also with brain imaging changes in T2-weighted magnetic resonance imaging and apparent diffusion coefficient that correspond to the location of apoptotic cell death. These results identify a critical role of XIAP in regulating neuronal apoptosis in vivo and demonstrate the enhanced vulnerability of neurons to injury in the absence of XIAP in the developing brain.
West
Tim
T
Department of Pediatrics, Washington University, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
Stump
Madeliene
M
Lodygensky
Gregory
G
Neil
Jeff J
JJ
Deshmukh
Mohanish
M
Holtzman
David M
DM
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D001284:Atrophy; D001921:Brain / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology*; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000172:deficiency*
D051636:X-Linked Inhibitor of Apoptosis Protein