Apoptosis in Neurons

Chuang, D M.

Abstract

We found that cerebellar granule cells (CGC) undergo spontaneous cell death after culturing in vitro for about 17 days. This cell death is characterized by DNA fragmentation, chromatin condensation, and requirement for RNA and protein synthesis, indicating the occurrence of apoptosis. This age-induced apoptosis is accelerated by N-methyl-D-aspartate (NMDA) but delayed by aurintricarboxylic acid (ATA), tetrahydroaminoacridine (THA), anti-oxidants and NMDA receptor antagonists. Overproduction of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA and protein precedes the cell death. This over-production is hastened by NMDA but diminished or prevented by ATA, THA, actinomycin-D or cycloheximide. Antisense oligodeoxyribonucleotides to GAPDH effectively protect against apoptosis, while the corresponding sense oligonucleotides are ineffective. Thus, GAPDH is linked to neuronal apoptosis. Cerebral cortical neurons also undergo age-induced apoptosis in culture and this form of cell death also involves GAPDH over-expression. Low potassium-induced apoptosis of CGC is blocked by cycloheximide and partially protected by actinomycin D, THA, and antisense oligonucleotides to GAPDH. Moreover, BDNF and bFGF provide efficient protection, while NT-3 is inactive. The neuroprotective effect of THA could be related to its therapeutic action in the treatment of Alzheimer's disease.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Mental Health (NIMH)
• Type: Intramural Research (Z01)
• Project #: 1Z01MH002698-01
• Application #: 5203836
• Support Year: 1
• Fiscal Year: 1995

Institution

• Name: U.S. National Institute of Mental Health
• Country: United States

Publications

Huang, Fengzhen; Zhang, Li; Long, Zhe et al. (2014) miR-25 alleviates polyQ-mediated cytotoxicity by silencing ATXN3. FEBS Lett 588:4791-8

Liang, Min-Huei; Chuang, De-Maw (2006) Differential roles of glycogen synthase kinase-3 isoforms in the regulation of transcriptional activation. J Biol Chem 281:30479-84

Leng, Yan; Chuang, De-Maw (2006) Endogenous alpha-synuclein is induced by valproic acid through histone deacetylase inhibition and participates in neuroprotection against glutamate-induced excitotoxicity. J Neurosci 26:7502-12

Chuang, De-Maw; Hough, Christopher; Senatorov, Vladimir V (2005) Glyceraldehyde-3-phosphate dehydrogenase, apoptosis, and neurodegenerative diseases. Annu Rev Pharmacol Toxicol 45:269-90

Chuang, De-Maw (2005) The antiapoptotic actions of mood stabilizers: molecular mechanisms and therapeutic potentials. Ann N Y Acad Sci 1053:195-204

Liang, Zhong-Qin; Wang, Xiao-Xia; Wang, Yumei et al. (2005) Susceptibility of striatal neurons to excitotoxic injury correlates with basal levels of Bcl-2 and the induction of P53 and c-Myc immunoreactivity. Neurobiol Dis 20:562-73

Peng, Giia-Sheun; Li, Guorong; Tzeng, Nian-Sheng et al. (2005) Valproate pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity in rat primary midbrain cultures: role of microglia. Brain Res Mol Brain Res 134:162-9

Leeds, P; Leng, Y; Chalecka-Franaszek, E et al. (2005) Neurotrophins protect against cytosine arabinoside-induced apoptosis of immature rat cerebellar neurons. Neurochem Int 46:61-72

Hiroi, T; Wei, H; Hough, C et al. (2005) Protracted lithium treatment protects against the ER stress elicited by thapsigargin in rat PC12 cells: roles of intracellular calcium, GRP78 and Bcl-2. Pharmacogenomics J 5:102-11

Ren, Ming; Leng, Yan; Jeong, MiRa et al. (2004) Valproic acid reduces brain damage induced by transient focal cerebral ischemia in rats: potential roles of histone deacetylase inhibition and heat shock protein induction. J Neurochem 89:1358-67