C-terminal mechano growth factor protects dopamine neurons: a novel peptide that induces heme oxygenase-1.
To assess potential efficacy of mechano growth factor (MGF) for chronic neurodegenerative disorders, we studied whether MGF protects dopamine (DA) neurons subjected to neurotoxic stress. We show that a short 24-amino acid C-terminal peptide of MGF (MGF24) upregulates heme oxygenase-1 (HO-1) expression and protects SH-SY5Y cells against apoptosis and cell loss induced by three DA cell-specific neurotoxins: 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenylpyridinium (MPP(+)), and rotenone. MGF24 maintains the mitochondrial membrane potential and blocks the release of mitochondrial apoptotic-inducing factor into the cytoplasm induced by 6-OHDA, MPP(+), and rotenone. Chemical inhibition of HO-1 with zinc protoporphyrin-IX prevents neuroprotection by MGF24 against the three neurotoxins. MGF24 does not activate Akt signaling nor does Akt inhibition block MGF24 protection of SH-SY5Y cells. In 6-OHDA-lesioned rats, central or peripheral MGF24 administration protects against the development of contralateral forelimb under-utilization, reduces ipsilateral nigral DA cell body loss, and attenuates tyrosine hydroxylase fiber loss in the ipsilateral striatum, independent of IGF-1 receptor activation. Peripheral MGF24 administration upregulates HO-1 expression in striatal and midbrain tissue. This report is the first to demonstrate that a small peptide, MGF24, upregulates HO-1, an important cell defense mediator, and protects DA cells, suggesting new strategies for neuroprotection in Parkinson's disease.
Quesada
Arnulfo
A
Research, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA. aquesada@mednet.ucla.edu
Micevych
Paul
P
Handforth
Adrian
A
D000818:Animals; D002460:Cell Line; D053938:DNA Fragmentation / Q000187:drug effects; D004298:Dopamine / Q000502:physiology*; D004790:Enzyme Induction / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D051336:Mitochondrial Membranes / Q000187:drug effects; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D018696:Neuroprotective Agents; D016627:Oxidopamine / Q000633:toxicity; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D050799:STAT5 Transcription Factor / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D013565:Sympatholytics / Q000633:toxicity; D013778:Tetrazolium Salts; D013844:Thiazoles; D025521:Tumor Suppressor Proteins / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D018696:Neuroprotective Agents; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; D013565:Sympatholytics; D013778:Tetrazolium Salts; D013844:Thiazoles; D025521:Tumor Suppressor Proteins; D007334:Insulin-Like Growth Factor I; D016627:Oxidopamine; D051547:Heme Oxygenase-1; D051057:Proto-Oncogene Proteins c-akt; C022616:thiazolyl blue; D004298:Dopamine