Cited by 163Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingNeuroinflammation and Neurodegeneration Mechanisms

Leptin Protects against 6-Hydroxydopamine-induced Dopaminergic Cell Death via Mitogen-activated Protein Kinase Signaling

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Weng, Zhongfang, Signore, Armando P., Gao, Yanqin, Wang, Suping, Zhang, Feng, Hastings, Teresa, Yin, Xiao-Ming, Chen, Jun·2007·Journal of Biological Chemistry

Abstract

The death of midbrain dopaminergic neurons in sporadic Parkinson disease is of unknown etiology but may involve altered growth factor signaling. The present study showed that leptin, a centrally acting hormone secreted by adipocytes, rescued dopaminergic neurons, reversed behavioral asymmetry, and restored striatal catecholamine levels in the unilateral 6-hydroxydopamine (6-OHDA) mouse model of dopaminergic cell death. In vitro studies using the murine dopaminergic cell line MN9D showed that leptin attenuated 6-OHDA-induced apoptotic markers, including caspase-9 and caspase-3 activation, internucleosomal DNA fragmentation, and cytochrome c release. ERK1/2 phosphorylation (pERK1/2) was found to be critical for mediating leptin-induced neuroprotection, because inhibition of the MEK pathway blocked both the pERK1/2 response and the pro-survival effect of leptin in cultures. Knockdown of the downstream messengers JAK2 or GRB2 precluded leptin-induced pERK1/2 activation and neuroprotection. Leptin/pERK1/2 signaling involved phosphorylation and nuclear localization of CREB (pCREB), a well known survival factor for dopaminergic neurons. Leptin induced a marked MEK-dependent increase in pCREB that was essential for neuroprotection following 6-OHDA toxicity. Transfection of a dominant negative MEK protein abolished leptin-enhanced pCREB formation, whereas a dominant negative CREB or decoy oligonucleotide diminished both pCREB binding to its target DNA sequence and MN9D survival against 6-OHDA toxicity. Moreover, in the substantia nigra of mice, leptin treatment increased the levels of pERK1/2, pCREB, and the downstream gene product BDNF, which were reversed by the MEK inhibitor PD98059. Collectively, these data provide evidence that leptin prevents the degeneration of dopaminergic neurons by 6-OHDA and may prove useful in the treatment of Parkinson disease.

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Crossref · 10.1074/jbc.m705426200

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Authors
Weng, Z., Signore, A. P., Gao, Y., Wang, S., Zhang, F., Hastings, T., Yin, X.-M., & Chen, J.
Affiliations
  • University of Pittsburgh (US)
  • Shanghai Medical College of Fudan University (CN)
Corresponding author
Chen, Jun
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2007-11
Volume
282
Issue
47
Pages
34479-34491
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2019752999
Cited by
163
References
62
Citations by year
2026: 2 · 2025: 4 · 2024: 4 · 2023: 3 · 2022: 11 · 2021: 10 · 2020: 7 · 2019: 8 · 2018: 10 · 2017: 8 · 2016: 13 · 2015: 8 · 2014: 14 · 2013: 10 · 2012: 11
FWCI
6.45
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Institute of Neurological Disorders and Stroke (NS 45048, NS 44178, NS43802, R01NS044178, R01NS045048, R01NS043802)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
leptin, dopaminergic neuron death, Parkinson's disease, 6-hydroxydopamine, ERK1/2 phosphorylation, MEK signaling, CREB, JAK2, Grb2, neuroprotection, apoptosis, substantia nigra, brain-derived neurotrophic factor, behavioral asymmetry
MeSH terms
Animals, Catecholamines, Cell Line, Cell Survival, Disease Models, Animal, Flavonoids, Humans, Neurons, Parkinson Disease, Phosphorylation, Substantia Nigra, Sympatholytics, Oxidopamine, Apoptosis, Adipocytes, Neuroprotective Agents, Mitogen-Activated Protein Kinase 1, Leptin, MAP Kinase Signaling System, Mitogen-Activated Protein Kinase 3, CREB-Binding Protein, Mice, GRB2 Adaptor Protein, Caspase 3, Caspase 9, Janus Kinase 2, DNA Fragmentation

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