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Cited by 41Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingProtein Kinase Regulation and GTPase Signaling

Rho GTPase regulation of α-synuclein and VMAT2: Implications for pathogenesis of Parkinson's disease

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Zhou, Zhigang, Kim, Jeeyong, Insolera, Ryan, Peng, Xiangmin, Fink, David J., Mata, Marina·2011·Molecular and Cellular Neuroscience
DOI 10.1016/j.mcn.2011.06.002PMC PMC3163163
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Abstract

Accumulation of α-synuclein (Asyn) in neuronal perikarya and dystrophic neurites is characteristic of idiopathic and familial Parkinson's disease. In this study, we investigated the relationship between α-synuclein expression and neurite outgrowth-maturation using MN9D dopaminergic cells and demonstrated key features of Asyn regulation in hippocampal neurons. Neurite elongation elicited by inhibition of Rho GTPase activity with C3 transferase or by db-cAMP treatment was associated with marked reduction of α-synuclein mRNA and protein expression. Rho inhibition resulted in reduction of transcription factor SRF in the nuclear fraction and retention of MKL-1 - the SRF co-transactivator of SRE - in cytosol, indicating that these effects of Rho inhibition may be mediated though reduction of SRF-SRE transcription. Inhibition of Rho GTPase activity led to decreased nuclear localization of GATA2, a key regulator of α-synuclein promoter activity. Rho inhibition-induced neurite extension was associated with increased VMAT2 and SNARE proteins synaptophysin and synapsin I. These results indicate that in the MN9D dopaminergic cell line, α-synuclein transcription and levels of synaptic vesicle associated proteins are inversely correlated with neurite growth. We confirm that in mature hippocampal neurons inhibition of RhoA and knock down of SRF by siRNA also lead to decrease GATA2 and Asyn. The results suggest that RhoA signaling may be potential therapeutic target for the treatment of synucleinopathies.

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  • RhoA inhibition reduces α-synuclein expression in MN9D dopaminergic cells.

    “RhoA inhibition has also been found to reduce α-synuclein expression in MN9D dopaminergic cells.”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [170]

  • The reduction of α-synuclein expression by RhoA inhibition is mediated through reduction in nuclear transcription factor SRF, its coactivator MKL-1, and GATA-2, a transcriptional regulator of α-synuclein.

    “This effect was mediated through the reduction in the nuclear transcription factor SRF, in its coactivator MKL-1, and in GATA-2, a transcriptional regulator of α-synuclein [170].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [170]

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Cited by

Sorted by citations

Authors
Zhou, Z., Kim, J., Insolera, R., Peng, X., Fink, D. J., & Mata, M.
Affiliations
University of Michigan (US)
Corresponding author
Mata, Marina
ORCID
Venue
Molecular and Cellular Neuroscience
Publisher
Elsevier BV
Published
2011-09
Volume
48
Issue
1
Pages
29-37
ISSN
1044-7431 (ISSN-L)
DOI
10.1016/j.mcn.2011.06.002
PMC
PMC3163163
OpenAlex
W2070643467
Cited by
41
References
1
Citations by year
2026: 2 · 2025: 3 · 2024: 4 · 2023: 3 · 2022: 3 · 2021: 1 · 2020: 4 · 2019: 2 · 2018: 1 · 2017: 2 · 2016: 4 · 2015: 1 · 2014: 4 · 2013: 4 · 2012: 3
FWCI
2.11
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Molecular and Cellular Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • Department of Veterans Affairs
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
Rho GTPases, RhoA, alpha-synuclein, vesicular monoamine transporter 2, Parkinson's disease, neurite outgrowth, SRF, GATA2, synaptophysin, synapsin I, synaptic vesicle proteins, transcriptional regulation, synucleinopathies, dopaminergic neurons, hippocampal neurons, C3 transferase, dibutyryl cyclic AMP
MeSH terms
Cyclic AMP, Animals, Cell Line, Enzyme Activation, Neurons, Parkinson Disease, Trans-Activators, Neurites, rho GTP-Binding Proteins, Serum Response Factor, Vesicular Monoamine Transport Proteins, GATA2 Transcription Factor, Mice, Protein Kinase C-alpha, alpha-Synuclein

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