Abstract |
Differential screening of gerbil brain hippocampal cDNA libraries was used to search for genes expressed in ischemic, but not normal, brain. The methylmalonyl-CoA mutase (MCM) cDNA was highly expressed after ischemia and showed a 95% similarity to mouse and 91% similarity to the human MCM cDNAs. Transient global ischemia induced a fourfold increase in MCM mRNA on Northern blots from both hippocampus and whole forebrain. MCM protein exhibited a similar induction on Western blots of gerbil cerebral cortex 8 and 24 hr after ischemia. Treatment of primary brain astrocytes with either the branched-chain amino acid (BCAA) isoleucine or the BCAA metabolite, propionate, induced MCM mRNA fourfold. Increased concentrations of BCAAs and odd-chain fatty acids, both of which are metabolized to propionate, may contribute to inducing the MCM gene during ischemia. Methylmalonic acid, which is formed from the MCM substrate methylmalonyl-CoA and which inhibits succinate dehydrogenase (SDH), produced dose-related cell death when injected into the basal ganglia of adult rat brain. This neurotoxicity is similar to that of structurally related mitochondrial SDH inhibitors, malonate and 3-nitropropionic acid. Methylmalonic acid may contribute to neuronal injury in human conditions in which it accumulates, including MCM mutations and B12 deficiency. This study shows that methylmalonyl-CoA mutase is induced by several stresses, including ischemia, and would serve to decrease the accumulation of an endogenous cellular mitochondrial inhibitor and neurotoxin, methylmalonic acid.
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Authors | P Narasimhan, R Sklar, M Murrell, R A Swanson, F R Sharp |
Journal | The Journal of neuroscience : the official journal of the Society for Neuroscience
(J Neurosci)
Vol. 16
Issue 22
Pg. 7336-46
(Nov 15 1996)
ISSN: 0270-6474 [Print] United States |
PMID | 8929440
(Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- DNA, Complementary
- Neurotoxins
- Propionates
- RNA, Messenger
- Isoleucine
- Methylmalonic Acid
- Methylmalonyl-CoA Mutase
- propionic acid
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Topics |
- Animals
- Basal Ganglia
(blood supply, cytology, metabolism)
- Base Sequence
- Blotting, Northern
- Blotting, Western
- Brain Chemistry
(physiology)
- Brain Ischemia
(physiopathology)
- Cell Death
(drug effects)
- DNA, Complementary
(analysis)
- Gene Expression Regulation, Developmental
(drug effects, physiology)
- Gene Expression Regulation, Enzymologic
(drug effects, physiology)
- Gerbillinae
- Isoleucine
(pharmacology)
- Male
- Methylmalonic Acid
(toxicity)
- Methylmalonyl-CoA Mutase
(genetics, metabolism)
- Microinjections
- Mitochondria
(chemistry, drug effects)
- Molecular Sequence Data
- Neurons
(cytology, drug effects, enzymology)
- Neurotoxins
(pharmacology)
- Oxidative Stress
(physiology)
- Propionates
(pharmacology)
- RNA, Messenger
(analysis)
- Sequence Homology, Amino Acid
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