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Induction of GDNF and BDNF by hRheb(S16H) Transduction of SNpc Neurons: Neuroprotective Mechanisms of hRheb(S16H) in a Model of Parkinson’s Disease

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Abstract

The transduction of dopaminergic (DA) neurons with human ras homolog enriched in brain, which has a S16H mutation [hRheb(S16H)] protects the nigrostriatal DA projection in the 6-hydroxydopamine (6-OHDA)-treated animal model of Parkinson’s disease (PD). However, it is still unclear whether the expression of active hRheb induces the production of neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), which are involved in neuroprotection, in mature neurons. Here, we show that transduction of nigral DA neurons with hRheb(S16H) significantly increases the levels of phospho-cyclic adenosine monophosphate (cAMP) response element-binding protein (p-CREB), GDNF, and BDNF in neurons, which are attenuated by rapamycin, a specific inhibitor of mammalian target of rapamycin complex 1 (mTORC1). Moreover, treatment with specific neutralizing antibodies for GDNF and BDNF reduced the protective effects of hRheb(S16H) against 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity. These results show that activation of hRheb/mTORC1 signaling pathway could impart to DA neurons the important ability to continuously produce GDNF and BDNF as therapeutic agents against PD.

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Abbreviations

6-OHDA:

6-Hydroxydopamine

AAV1:

Adeno-associated virus 1

ANOVA:

Analysis of variance

AP:

Anterior-posterior

BDNF:

Brain-derived neurotrophic factor

DA:

Dopaminergic

DAPI:

4′,6-Diamidino-2-phenylindole

DV:

Dorsal-ventral

FLAG:

FLAG-tag

GDNF:

Glial cell line-derived neurotrophic factor

GFAP:

Glial fibrillary acidic protein

GFP:

Green fluorescent protein

hRheb(S16H):

Human Ras homolog enriched in brain with a S16H mutation

ip:

Immunopositive

MFB:

Medial forebrain bundle

ML:

Medial-lateral

MPP+ :

1-Methyl-4-phenylpyridinium

mTORC1:

Mammalian target of rapamycin complex 1

p-CREB:

Phospho-cAMP response element binding protein

PBS:

Phosphate-buffered saline

PD:

Parkinson’s disease

SD:

Sprague-Dawley

SN:

Substantia nigra

SNpc:

Substantia nigra pars compacta

STR:

Striatum

TH:

Tyrosine hydroxylase

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Acknowledgments

This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (Nos. 2008-0061888 and 2012R1A1A1039140).

Conflict of Interest

The authors declare no conflicts of interest.

Author information

Authors and Affiliations

  1. School of Life Sciences, KNU Creative BioResearch Group (BK21 plus program), Kyungpook National University, Daegu, 702-701, Korea

    Eunju Leem, Min-Tae Jeon, Kyoung Hoon Jeong, Jeen-Woo Park & Sang Ryong Kim

  2. Department of Neuroscience, Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul, 130-701, Korea

    Jin Han Nam & Byung Kwan Jin

  3. Center for Food and Nutritional Genomics Research, Kyungpook National University, Daegu, 702-701, Korea

    Un Ju Jung

  4. Department of Neurology, Columbia University, New York, NY, 10032, USA

    Nikolai Kholodilov & Robert E. Burke

  5. Pathology and Cell Biology, Columbia University, New York, NY, 10032, USA

    Robert E. Burke

  6. Brain Science and Engineering Institute, Kyungpook National University, Daegu, 700-842, Korea

    Sang Ryong Kim

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  1. Jin Han Nam
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  2. Eunju Leem
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Corresponding authors

Correspondence to Byung Kwan Jin or Sang Ryong Kim.

Additional information

Jin Han Nam Eunju Leem and Min-Tae Jeon contributed equally to this work.

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Nam, J.H., Leem, E., Jeon, MT. et al. Induction of GDNF and BDNF by hRheb(S16H) Transduction of SNpc Neurons: Neuroprotective Mechanisms of hRheb(S16H) in a Model of Parkinson’s Disease. Mol Neurobiol 51, 487–499 (2015). https://doi.org/10.1007/s12035-014-8729-2

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  • DOI: https://doi.org/10.1007/s12035-014-8729-2

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