GABAergic striatal neurons exhibit caspase-independent, mitochondrially mediated programmed cell death.
GABAergic striatal neurons are compromised in basal ganglia pathologies and we analysed how insult nature determined their patterns of injury and recruitment of the intrinsic mitochondrial pathway during programmed cell death (PCD). Stressors affecting targets implicated in striatal neurodegeneration [3-morpholinylsydnoneimine (SIN-1), 3-nitropropionic acid (3-NP), NMDA, 3,5-dihydroxyphenylglycine (DHPG), and staurosporine (STS)] were compared in cultured GABAergic neurons from murine striatum by analyzing the progression of injury and its correlation with mitochondrial involvement, the redistribution of intermembrane space (IMS) proteins, and patterns of protease activation. Stressors produced PCD exhibiting slow-onset kinetics with time-dependent annexin-V labeling and eventual DNA fragmentation. IMS proteins including cytochrome c were differentially distributed, although stressors except STS produced early redistribution of apoptosis-inducing factor and Omi, suggestive of early recruitment of both caspase-dependent and caspase-independent signaling. In general, Bax mobilization to mitochondria appeared to promote IMS protein redistribution. Caspase 3 activation was prominent after STS, whereas NMDA and SIN-1 produced mainly calpain activation, and 3-NP and DHPG elicited a mixed profile of protease activation. PCD and redistribution of IMS proteins in striatal GABAergic neurons were canonical and insult-dependent, reflecting differential interplay between the caspase cascade and alternate cell death pathways.
Diwakarla
Shanti
S
Brain Injury and Repair Program, Florey Neuroscience Institutes, The University of Melbourne, Parkville, Victoria, Australia.
Mercer
Linda D
LD
Kardashsyan
Liubov
L
Chu
Percy W Y
PW
Shin
Yea Seul
YS
Lau
Chew L
CL
Hughes
Maria L R
ML
Nagley
Phillip
P
Beart
Philip M
PM
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002154:Calpain / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D020169:Caspases / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D053938:DNA Fragmentation; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011247:Pregnancy; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D008565:Membrane Proteins; D005680:gamma-Aminobutyric Acid; D002154:Calpain; D053148:Caspase 3; D020169:Caspases