Leptin Protects against 6-Hydroxydopamine-induced Dopaminergic Cell Death via Mitogen-activated Protein Kinase Signaling
Open accessAbstract
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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Leptin signaling has an important role in preserving the dopaminergic system.
“leptin signaling also has an important role in preserving the dopaminergic system.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [592]
Cites
Leptin and the regulation of body weight in mammals
Friedman, J. M., & Halaas, J. L. (1998) · Nature · doi:10.1038/27376 · Cited by 5,405 · see citing works
Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis
Xia, Z., Dickens, M., Raingeaud, J., Davis, R. J., & Greenberg, M. E. (1995) · Science · doi:10.1126/science.270.5240.1326 · Cited by 5,290 · see citing works
Weight-Reducing Effects of the Plasma Protein Encoded by the <i>obese</i> Gene
Halaas, J. L., Gajiwala, K. S., Maffei, M., Cohen, S. L., Chait, B. T., Rabinowitz, D., Lallone, R. L., Burley, S. K., & Friedman, J. M. (1995) · Science · doi:10.1126/science.7624777 · Cited by 4,451 · see citing works
A System for Stable Expression of Short Interfering RNAs in Mammalian Cells
Brummelkamp, T. R., Bernards, R., & Agami, R. (2002) · Science · doi:10.1126/science.1068999 · Cited by 4,295 · see citing works
NEURAL MECHANISMS OF ADDICTION: The Role of Reward-Related Learning and Memory
Hyman, S. E., Malenka, R. C., & Nestler, E. J. (2006) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.29.051605.113009 · Cited by 2,647 · see citing works
Bonni, A., Brunet, A., West, A. E., Datta, S. R., Takasu, M. A., & Greenberg, M. E. (1999) · Science · doi:10.1126/science.286.5443.1358 · Cited by 1,887 · see citing works
Gundersen, H. J. G. (1986) · PubMed · Cited by 1,659 · see citing works
Ca2+ Influx Regulates BDNF Transcription by a CREB Family Transcription Factor-Dependent Mechanism
Tao, X., Finkbeiner, S., Arnold, D. B., Shaywitz, A. J., & Greenberg, M. E. (1998) · Neuron · doi:10.1016/s0896-6273(00)81010-7 · Cited by 1,561 · see citing works
Stereology of arbitrary particles*
Gundersen, H. J. G. (1986) · Journal of Microscopy · doi:10.1111/j.1365-2818.1986.tb02764.x · Cited by 1,444 · see citing works
Carlezon, W. A., Duman, R. S., & Nestler, E. J. (2005) · Trends in Neurosciences · doi:10.1016/j.tins.2005.06.005 · Cited by 1,351 · see citing works
Leptin enters the brain by a saturable system independent of insulin
Banks, W. A., Kastin, A. J., Huang, W., Jaspan, J. B., & Maness, L. M. (1996) · Peptides · doi:10.1016/0196-9781(96)00025-3 · Cited by 1,222 · see citing works
Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo
Tomac, A., Lindqvist, E., Lin, L.-F. H., Ögren, S. O., Young, D., Hoffer, B. J., & Olson, L. (1995) · Nature · doi:10.1038/373335a0 · Cited by 1,079 · see citing works
Leptin Receptor Signaling in Midbrain Dopamine Neurons Regulates Feeding
Hommel, J. D., Trinko, R., Sears, R. M., Georgescu, D., Liu, Z.-W., Gao, X.-B., Thurmon, J. J., Marinelli, M., & DiLeone, R. J. (2006) · Neuron · doi:10.1016/j.neuron.2006.08.023 · Cited by 902 · see citing works
Mercer, J. G., Hoggard, N., Williams, L. M., Lawrence, C. B., Hannah, L. T., & Trayhurn, P. (1996) · FEBS Letters · doi:10.1016/0014-5793(96)00473-5 · Cited by 880 · see citing works
Activation of Downstream Signals by the Long Form of the Leptin Receptor
Banks, A. S., Davis, S. M., Bates, S. H., & Myers, M. G. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.19.14563 · Cited by 797 · see citing works
Chen, J., Nagayama, T., Jin, K., Stetler, R. A., Zhu, R. L., Graham, S. H., & Simon, R. P. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-13-04914.1998 · Cited by 704 · see citing works
Self-citationSchneider, A., Krüger, C., Steigleder, T., Weber, D., Pitzer, C., Laage, R., Aronowski, J. A., Maurer, M. H., Gaßler, N., Mier, W., et al. (2005) · Journal of Clinical Investigation · doi:10.1172/jci23559 · Cited by 691 · see citing works
Leptin Regulation of the Mesoaccumbens Dopamine Pathway
Fulton, S., Pissios, P., Manchon, R. P., Stiles, L., Frank, L., Pothos, E. N., Maratos-Flier, E., & Flier, J. S. (2006) · Neuron · doi:10.1016/j.neuron.2006.09.006 · Cited by 644 · see citing works
Imada, K., & Leonard, W. J. (2000) · Molecular Immunology · doi:10.1016/s0161-5890(00)00018-3 · Cited by 610 · see citing works
Enwere, E. K., Shingo, T., Gregg, C., Fujikawa, H., Ohta, S., & Weiss, S. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.2751-04.2004 · Cited by 549 · see citing works
Is CREB a key to neuronal survival?
Walton, M. R., & Dragunow, M. (2000) · Trends in Neurosciences · doi:10.1016/s0166-2236(99)01500-3 · Cited by 520 · see citing works
Figlewicz, D. P., Evans, S. B., Murphy, J., Hoen, M., & Baskin, D. G. (2003) · Brain Research · doi:10.1016/s0006-8993(02)04087-8 · Cited by 482 · see citing works
Localization of specific erythropoietin binding sites in defined areas of the mouse brain.
Digicaylioglu, M. H., Bichet, S., Marti, H. H., et al. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.9.3717 · Cited by 480 · see citing works
Spina, M. B., Squinto, S. P., Miller, J. M., Lindsay, R. M., & Hyman, C. (1992) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1992.tb08880.x · Cited by 460 · see citing works
A test for detecting long-term sensorimotor dysfunction in the mouse after focal cerebral ischemia
Zhang, L., Schallert, T. J., Zhang, Z. G., Jiang, Q., Arniego, P., Li, Q., Lü, M., & Chopp, M. (2002) · Journal of Neuroscience Methods · doi:10.1016/s0165-0270(02)00114-0 · Cited by 411 · see citing works
Mogi, M., Togari, A., Kondo, T., Mizuno, Y., Komure, O., Kuno, S., Ichinose, H., & Nagatsu, T. (1999) · Neuroscience Letters · doi:10.1016/s0304-3940(99)00463-2 · Cited by 394 · see citing works
Brennan, A. M., & Mantzoros, C. S. (2006) · Nature Clinical Practice Endocrinology & Metabolism · doi:10.1038/ncpendmet0196 · Cited by 374 · see citing works
Divergent Roles of SHP-2 in ERK Activation by Leptin Receptors
Bjørbæk, C., Buchholz, R. M., Davis, S. M., Bates, S. H., Pierroz, D. D., Gu, H., Neel, B. G., Myers, M. G., & Flier, J. S. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m007439200 · Cited by 364 · see citing works
Larsen, K. E., Fon, E. A., Hastings, T. G., Edwards, R. H., & Sulzer, D. L. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-20-08951.2002 · Cited by 335 · see citing works
Self-citationParain, K., Murer, M. G., Yan, Q., Faucheux, B. A., Agid, Y., Hirsch, É. C., & Raisman‐Vozari, R. (1999) · Neuroreport · doi:10.1097/00001756-199902250-00021 · Cited by 303 · see citing works
Tardito, D., Perez, J., Tiraboschi, E., Musazzi, L., Racagni, G., & Popoli, M. (2006) · Pharmacological Reviews · doi:10.1124/pr.58.1.7 · Cited by 303 · see citing works
Role of extracellular signal regulated kinases 1 and 2 in neuronal survival
Hetman, M., & Góźdź, A. (2004) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.2004.04133.x · Cited by 274 · see citing works
Leptin‐induced signal transduction pathways
Hegyi, K., Fülöp, K., Kovács, K., Tóth, S., & Falus, A. (2004) · Cell Biology International · doi:10.1016/j.cellbi.2003.12.003 · Cited by 246 · see citing works
Saxena, N. K., Titus, M. A., Ding, X., Floyd, J. J., Srinivasan, S., Sitaraman, S. V., & Anania, F. A. (2004) · The FASEB Journal · doi:10.1096/fj.04-1847fje · Cited by 211 · see citing works
Luo, Y., Yin, W., Signore, A. P., Zhang, F., Hong, Z., Wang, S., Graham, S. H., & Chen, J. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.03758.x · Cited by 203 · see citing works
Self-citationSon, J. H., Chun, H. S., JOH, T. H., Cho, S., Conti, B., & Lee, J. W. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-01-00010.1999 · Cited by 195 · see citing works
Bensadoun, J., Déglon, N., Tseng, J., Ridet, J., Zurn, A. D., & Aebischer, P. (2000) · Experimental Neurology · doi:10.1006/exnr.2000.7409 · Cited by 183 · see citing works
Oncoprotein Akt/PKB induces trophic effects in murine models of Parkinson's disease
Ries, V., Henchcliffe, C., Kareva, T., Rzhetskaya, M., Bland, R. J., During, M. J., Kholodilov, N. G., & Burke, R. E. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0606401103 · Cited by 168 · see citing works
Leptin inhibits stress-induced apoptosis of T lymphocytes
FUJITA, Y., MURAKAMI, M., Ogawa, Y., Masuzaki, H., Tanaka, M., OZAKI, S., Nakao, K., & Mimori, T. (2002) · Clinical & Experimental Immunology · doi:10.1046/j.1365-2249.2002.01797.x · Cited by 157 · see citing works
Rouet‐Benzineb, P., Aparicio, T., Guilmeau, S., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m312999200 · Cited by 148 · see citing works
Leptin acts as a mitogenic and antiapoptotic factor for colonic cancer cells
Hoda, M. R., Keely, S. J., Bertelsen, L. S., JUNGER, W. G., Dharmasena, D., & Barrett, K. E. (2007) · British journal of surgery · doi:10.1002/bjs.5530 · Cited by 137 · see citing works
Ding, Y. M., Jaumotte, J. D., Signore, A. P., & Zigmond, M. J. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02415.x · Cited by 137 · see citing works
Self-citationInduction of brain-derived neurotrophic factor by leptin in the ventromedial hypothalamus
Komori, T., Morikawa, Y., Nanjo, K., & Senba, E. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2005.12.066 · Cited by 122 · see citing works
A Novel Neuroprotectant Granulocyte-Colony Stimulating Factor
Solaroğlu, İ., Cahill, J., Jadhav, V. R., et al. (2006) · Stroke · doi:10.1161/01.str.0000208205.26253.96 · Cited by 120 · see citing works
Functional Repression of cAMP Response Element in 6-Hydroxydopamine-treated Neuronal Cells*
Chalovich, E. M., Zhu, J.-H., Caltagarone, J., Bowser, R., & Chu, C. T. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m602632200 · Cited by 108 · see citing works
Thioredoxin as a neurotrophic cofactor and an important regulator of neuroprotection
Masutani, H., Bai, J., Kim, Y.-C., & Yodoi, J. (2004) · Molecular Neurobiology · doi:10.1385/mn:29:3:229 · Cited by 107 · see citing works
Erythropoietin protects against 6‐hydroxydopamine‐induced dopaminergic cell death
Signore, A. P., Weng, Z., Hastings, T. G., et al. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03587.x · Cited by 90 · see citing works
Self-citationNeuroprotective effects of leptin in vivo and in vitro
Dicou, E., Attoub, S., & Gressèns, P. (2001) · Neuroreport · doi:10.1097/00001756-200112210-00019 · Cited by 87 · see citing works
Cavanaugh, J. E., Jaumotte, J. D., Lakoski, J. M., & Zigmond, M. J. (2006) · Journal of Neuroscience Research · doi:10.1002/jnr.21024 · Cited by 86 · see citing works
Chu, C. T., Zhu, J., Cao, G., et al. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03329.x · Cited by 83 · see citing works
Troadec, J., Marien, M. R., Mourlevat, S., Debeir, T., Ruberg, M., Colpaert, F. C., & Michel, P. P. (2002) · Molecular Pharmacology · doi:10.1124/mol.62.5.1043 · Cited by 79 · see citing works
Effective gene delivery to adult neurons by a modified form of electroporation
Leclere, P. G., Panjwani, A., Docherty, R. J., et al. (2004) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2004.08.012 · Cited by 66 · see citing works
Development of leptin antagonists and their potential use in experimental biology and medicine
Gertler, A. (2006) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2006.09.006 · Cited by 62 · see citing works
Influence of Cocaine on the JAK–STAT Pathway in the Mesolimbic Dopamine System
Berhow, M. T., Hiroi, N., Kobierski, L. A., Hyman, S. E., & Nestler, E. J. (1996) · Journal of Neuroscience · doi:10.1523/jneurosci.16-24-08019.1996 · Cited by 61 · see citing works
Kurrimbux, D., Gaffen, Z. A., Farrell, C. L., Martin, D. K., & Thomas, S. A. (2003) · Neuroscience · doi:10.1016/j.neuroscience.2003.08.061 · Cited by 61 · see citing works
Leptin inhibits 1-methyl-4-phenylpyridinium-induced cell death in SH-SY5Y cells
Lu, J., Park, C., Lee, S., Shin, D. W., & Kang, J. (2006) · Neuroscience Letters · doi:10.1016/j.neulet.2006.08.053 · Cited by 51 · see citing works
Mütze, J., Roth, J., Gerstberger, R., Matsumura, K., & Hübschle, T. (2005) · Neuroscience Letters · doi:10.1016/j.neulet.2005.10.031 · Cited by 40 · see citing works
Liang, Q., Liou, A. K. F., Ding, Y., et al. (2004) · Journal of Neuroscience Research · doi:10.1002/jnr.20198 · Cited by 39 · see citing works
Selective vulnerability in adult and ageing mammalian neurons
Cowen, T. (2002) · Autonomic Neuroscience · doi:10.1016/s1566-0702(01)00376-9 · Cited by 37 · see citing works
Ditlevsen, D. K., Berezin, V., & Bock, E. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2007.05436.x · Cited by 35 · see citing works
Elmquist (1998) · doi:10.1002/(sici)1096-9861(19980615)395:4
?imi?, G., Kostovi?, I., Winblad, B., & Bogdanovi?, N. (1997) · The Journal of Comparative Neurology · doi:10.1002/(sici)1096-9861(19970324)379:4
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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
- hybrid
- doi.org
- Licence
- 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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