Aldolase C-positive cerebellar Purkinje cells are resistant to delayed death after cerebral trauma and AMPA-mediated excitotoxicity.
The cerebellum has been shown to be vulnerable to global ischemic damage in tightly controlled zones of Purkinje cells (PCs) that lack aldolase C, an enzyme critical for glycolysis. Here, we investigated whether aldolase C-negative PCs were more likely to die after cerebral trauma in vivo, and whether this death was mediated by excitotoxic [alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-mediated] means in vitro. Mice were subjected to controlled cortical impact, or remained uninjured, and were killed at 6 h, 24 h or 7 days after injury. Cerebellar sections (both ipsilateral and contralateral to the site of cerebral injury) were stained against aldolase C and calbindin (a marker of PCs). The number of viable, calbindin-positive PCs decreased significantly at 24 h and 7 days after injury, and the percentage of surviving, aldolase C-positive PCs significantly increased at those time-points. In addition, we subjected murine cerebellar cultures to AMPA (30 microm, 20 min), which killed a significant number of PCs at 24 h post-treatment. A similar number of PCs was lost after transfection with aldolase C siRNA, and this effect was exacerbated in transfected cultures treated with AMPA. The results from the present study indicate that aldolase C provides marked neuroprotection to PCs after trauma and excitotoxicity.
Department of Neuroscience, Erasmus Medical Centre, Rotterdam, The Netherlands.
Jennifer E
JE
Slemmer
Elize D
ED
Haasdijk
Doortje C
DC
Engel
Nikolaus
N
Plesnila
John T
JT
Weber
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001930:Brain Injuries / Q000201:enzymology*; D064026:Calbindins; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004351:Drug Resistance / Q000187:drug effects / Q000502:physiology*; D004357:Drug Synergism; D050581:Excitatory Amino Acid Transporter 4 / Q000096:biosynthesis; D005634:Fructose-Bisphosphate Aldolase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000201:enzymology*; D009498:Neurotoxins / Q000633:toxicity; D011689:Purkinje Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000633:toxicity; D064030:S100 Calcium Binding Protein G / Q000096:biosynthesis; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity
D015415:Biomarkers; D064026:Calbindins; D050581:Excitatory Amino Acid Transporter 4; D009498:Neurotoxins; D034741:RNA, Small Interfering; D064030:S100 Calcium Binding Protein G; C493390:Slc1a6 protein, mouse; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D005634:Fructose-Bisphosphate Aldolase