Cited by 250Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingDeep Brain Stimulation and Movement Disorders

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α-Synuclein activation of protein phosphatase 2A reduces tyrosine hydroxylase phosphorylation in dopaminergic cells

Peng, Xiangmin M., Tehranian, Roya, Dietrich, Paula, Stefanis, Leonidas, Perez, Ruth G.·2005·Journal of Cell Science

DOI 10.1242/jcs.02481

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Abstract

α-Synuclein is an abundant presynaptic protein implicated in neuronal plasticity and neurodegenerative diseases. Although the function of α-synuclein is not thoroughly elucidated, we found that α-synuclein regulates dopamine synthesis by binding to and inhibiting tyrosine hydroxylase, the rate limiting enzyme in dopamine synthesis. Understanding α-synuclein function in dopaminergic cells should add to our knowledge of this key protein, which is implicated in Parkinson's disease and other disorders. Herein, we report a mechanism by which α-synuclein diminishes tyrosine hydroxylase phosphorylation and activity in stably transfected dopaminergic cells. Short-term regulation of tyrosine hydroxylase depends on the phosphorylation of key seryl residues in the amino-terminal regulatory domain of the protein. Of these, Ser40 contributes significantly to tyrosine hydroxylase activation and dopamine synthesis. We observed that α-synuclein overexpression caused reduced Ser40 phosphorylation in MN9D cells and inducible PC12 cells. Ser40 is phosphorylated chiefly by the cyclic AMP-dependent protein kinase PKA and dephosphorylated almost exclusively by the protein phosphatase, PP2A. Therefore, we measured the impact of α-synuclein overexpression on levels and activity of PKA and PP2A in our cells. PKA was unaffected by α-synuclein. PP2A protein levels also were unchanged, however, the activity of PP2A increased in parallel with α-synuclein expression. Inhibition of PP2A dramatically increased Ser40 phosphorylation only in α-synuclein overexpressors in which α-synuclein was also found to co-immunoprecipitate with PP2A. Together the data reveal a functional interaction between α-synuclein and PP2A that leads to PP2A activation and underscores a key role for α-synuclein in protein phosphorylation.

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“α-Synuclein (α-Syn), a protein highly enriched in presynaptic terminals (Maroteaux et al., 1988), is implicated in normal brain function (George et al., 1989) as well as disease (reviewed by Perez and Hastings, 2004).”
Background
Ceramide activates heterotrimeric protein phosphatase 2A
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Background
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“Control MN9D cells with low endogenous levels of α-Syn, included both untransfected parental MN9D cells and MN9D cells stably transfected with either pcDNA3 or GFP vector (Perez et al., 2002).”
BackgroundInfluentialSelf-citation
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MethodSelf-citation
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Background
Molecular cloning of cDNA coding for brain-specific 14-3-3 protein, a protein kinase-dependent activator of tyrosine and tryptophan hydroxylases.
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“Previously, we noted that α-Syn acts to inhibit TH phosphorylation and dopamine synthesis in vitro [31,33].”
BackgroundMethodInfluentialSelf-citation
Immunological features of α‐synuclein in Parkinson's disease
Roodveldt, C., Christodoulou, J., & Dobson, C. M. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00450.x · Cited by 97
“It is known to interact with a variety of proteins [13, 14] and also with lipid vesicles [15], and it may be involved in lipid metabolism [16, 17].”
Background
Mitochondrial Dysfunction: The Road to Alpha-Synuclein Oligomerization in PD
Esteves, A. R., Arduíno, D. M., Silva, D. F., Oliveira, C. R., & Cardoso, S. M. (2011) · Parkinson s Disease · doi:10.4061/2011/693761 · Cited by 90
“It is thought that alpha-syn plays a role in the regulation of dopamine biosynthesis via activation of protein phosphatase 2A that reduces tyrosine hydroxylase phosphorylation, the rate-limiting enzyme in dopamine production [158, 159], and reducing the amount of available active mitogen-activated protein kinases [160…”
α-Synuclein binds the KATP channel at insulin-secretory granules and inhibits insulin secretion
Geng, X., Lou, H., Wang, J., Li, L., Swanson, A., Sun, M., Beers-Stolz, D., Watkins, S. C., Perez, R. G., & Drain, P. F. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00262.2010 · Cited by 90
“All steps were carried out at 4°C as previously described (46, 47), with minor modifications.”
BackgroundMethodSelf-citation
Retracted: Differential effects of 24‐hydroxycholesterol and 27‐hydroxycholesterol on tyrosine hydroxylase and α‐synuclein in human neuroblastoma SH‐SY5Y cells
Prasanthi, J. R. P., Feist, G., Thomasson, S., Thompson, A. J., Schommer, E., & Ghribi, O. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05736.x · Cited by 91
Retracted
Alpha-Synuclein Post-translational Modifications: Implications for Pathogenesis of Lewy Body Disorders
Manzanza, N. D. O., Sedlackova, L., & Kalaria, R. N. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.690293 · Cited by 98
“…et al., 2015; Sharma et al., 2015 Regulation of DA biosynthesis Protein phosphatase 2A Inhibition of tyrosine Hydroxylase Regulation of DA levels Peng et al., 2005; Yang et al., 2013 Suppression of apoptosis Protein C Kinase Deactivation of NFkB Neuroprotection Jin et al., 2011 SNARE,…”
Background
Tyrosine hydroxylase phosphorylation in vivo
Dunkley, P. R., & Dickson, P. W. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14675 · Cited by 90
“The decreases in TH phosphorylation at Ser40 are not because of decreases in PKA activity, but rather to increases in PP2A activity (Peng et al. 2005).”
BackgroundInfluential
Dynamic structural flexibility of α-synuclein
Mor, D. E., Ugras, S. E., Daniels, M. J., & Ischiropoulos, H. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.12.018 · Cited by 85
α-Synuclein transgenic mice exhibit reduced anxiety-like behaviour
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Alpha-synuclein modulates dopamine neurotransmission
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RETRACTED: The oxysterol 27‐hydroxycholesterol regulates α‐synuclein and tyrosine hydroxylase expression levels in human neuroblastoma cells through modulation of liver X receptors and estrogen receptors–relevance to Parkinson’s disease
Marwarha, G., Rhen, T., Schommer, T., & Ghribi, O. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07497.x · Cited by 85
“(2011) 119, 1119–1136 1119 well as decreased TH expression (Yu et al. 2004; Gao et al. 2007) and activity (Perez et al. 2002; Peng et al. 2005).”
Retracted
A calcineurin- and NFAT-dependent pathway is involved in -synuclein-induced degeneration of midbrain dopaminergic neurons
Luo, J., Sun, L., Lin, X., Liu, G., Yu, J., Parisiadou, L., Xie, C., Ding, J., & Cai, H. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu377 · Cited by 79
Can Interactions Between α-Synuclein, Dopamine and Calcium Explain Selective Neurodegeneration in Parkinson's Disease?
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“, 2010), which was modulated by the activity of protein phosphatase 2A (Peng et al., 2005).”
Background
Neuroprotective and Anti-inflammatory Properties of a Coffee Component in the MPTP Model of Parkinson's Disease
Lee, K., Im, J., Woo, J. J., Jasutkar, H. G., Kim, Y., Cristóvão, A. C., Sonsalla, P. K., Schuster, D. S., Jalbut, M. M., Fernández, J. R., et al. (2013) · Neurotherapeutics · doi:10.1007/s13311-012-0165-2 · Cited by 78
“Additionally, normalization of PP2A function has been hypothesized to be relevant in relation to modulation of tyrosine hydroxylase function [37, 38].”
Background
14-3-3ζ Contributes to Tyrosine Hydroxylase Activity in MN9D Cells
Wang, J., Lou, H., Pedersen, C. J., Smith, A. D., & Perez, R. G. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m901310200 · Cited by 75
Self-citation
Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease and Dopa-Responsive Dystonia
Kawahata, I., & Fukunaga, K. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21113779 · Cited by 71
Involvement of ERK1/2 signaling pathway in DJ-1-induced neuroprotection against oxidative stress
Gu, L., Cui, T., Fan, C., Zhao, H., Zhao, C., Lu, L., & Yang, H. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.04.037 · Cited by 74
“a-Synuclein was found to co-immunoprecipitate with PP2A [22] and we found that the expression of PP2A was modulated by a-synuclein (data not shown).”
Background
The role of lipids in α-synuclein misfolding and neurotoxicity
Ugalde, C. L., Lawson, V., Finkelstein, D. I., & Hill, A. F. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.rev119.007500 · Cited by 77
Anti-Parkinson's disease activity of phenolic acids from Eucommia ulmoides Oliver leaf extracts and their autophagy activation mechanism
Zhang, S., Yu, Z., Xia, J., Zhang, X., Liu, K., Attila Gabor, S. I. K., & Jin, M. (2019) · Food & Function · doi:10.1039/c9fo02288k · Cited by 72
FTY720/Fingolimod Reduces Synucleinopathy and Improves Gut Motility in A53T Mice
Vidal-Martínez, G., Vargas‐Medrano, J., Gil-Tommee, C., Medina, D. X., Garza, N. T., Yang, B. C., Segura‐Ulate, I., Dominguez, S. J., & Perez, R. G. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.744029 · Cited by 72
Self-citation
Dynamics of tyrosine hydroxylase mediated regulation of dopamine synthesis
Kaushik, P., Gorin, F. A., & Vali, S. (2006) · Journal of Computational Neuroscience · doi:10.1007/s10827-006-0004-8 · Cited by 76
Alpha-Synuclein Contribution to Neuronal and Glial Damage in Parkinson’s Disease
Saramowicz, K., Siwecka, N., Galita, G., Kucharska-Lusina, A., Rozpędek‐Kamińska, W., & Majsterek, I. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms25010360 · Cited by 79
“In vitro studies have shown that α Syn overexpression leads to downregulation of crucial enzymes involved in DA biosynthesis (tyrosine hydroxylase and aromatic amino acid decarboxylase), as well as an impairment of dopamine transporter (DAT) reuptake activity [125–127].”
A new role for α‐synuclein in Parkinson's disease: Alteration of ER–mitochondrial communication
Guardia‐Laguarta, C., Área-Gómez, E., Schon, E. A., & Przedborski, S. (2015) · Movement Disorders · doi:10.1002/mds.26239 · Cited by 70
“Given that a-Syn associates with PP2A,(115) perhaps the phosphorylation status of both proteins is mediated in a reciprocal way, via PP2A, a possibility proposed by others.(58,115,117,119) What connection might there be among the phosphorylation of a-Syn, TH activity, PP2A activity, and MAM? First, we propose that the…”
Background
Biochemical increase in phosphorylated alpha-synuclein precedes histopathology of Lewy-type synucleinopathies
Lue, L., Walker, D. G., Adler, C., Shill, H. A., Tran, H., Akiyama, H., Sue, L., Caviness, J., Sabbagh, M. N., & Beach, T. G. (2012) · Brain Pathology · doi:10.1111/j.1750-3639.2012.00585.x · Cited by 65
“By inhibition of the enzyme that dephosphorylates TH, called phosphor-protein phosphatase 2A (PP2A), asyn promotes the activity of the TH (47).”
Background
LRRK2 Phosphorylation, More Than an Epiphenomenon
Marchand, A., Drouyer, M., Sarchione, A., Chartier‐Harlin, M., & Taymans, J. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00527 · Cited by 70
“…| www.frontiersin.org 13 June 2020 | Volume 14 | Article 527 (Reynolds et al., 2014) without affecting the protein level of PP2A in cell lines (Peng et al., 2005), but on the other hand, increased oligomerization and phosphorylation of α-syn reduced the activity of PP2A (Lou et al., 2010;…”
Background
Akt as a Victim, Villain and Potential Hero in Parkinson’s Disease Pathophysiology and Treatment
Greene, L. A., Levy, O., & Malagelada, C. (2011) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-011-9671-8 · Cited by 69
“Of relevance to this, the activity/level of protein phosphatase 2A (PP2A), for which phospho-Akt is a substrate, is elevated by alpha synuclein (Peng et al. 2005) and in response to 6-OHDA (Ryu et al. 2005; Chung et al. 2007) in cultured cells.”
Up-regulation of autophagy-related gene 5 (ATG5) protects dopaminergic neurons in a zebrafish model of Parkinson's disease
Hu, Z., Chen, B., Zhang, J., & Ma, Y. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.764795 · Cited by 68
Intrinsically disordered proteins may escape unwanted interactions via functional misfolding
Uversky, V. N. (2011) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2011.03.010 · Cited by 68
Non‐motor parkinsonian pathology in aging A53T α‐Synuclein mice is associated with progressive synucleinopathy and altered enzymatic function
Farrell, K., Krishnamachari, S., Villanueva, E., Lou, H., Alerte, T. N. M., Peet, E., Drolet, R. E., & Perez, R. G. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12481 · Cited by 63
“Inhibitors for specificity included: 50 nM protein-phosphataseinhibitor 2 (PP1-specific), 3 nM fostriecin (PP2A/PP4-specific), 50 nM cantharidin (PP4-specific), and 10 nM okadaic acid as previously described (Peng et al. 2005; Lou et al. 2010; Wu et al. 2012).”
InfluentialSelf-citation
Dichotomy of Tyrosine Hydroxylase and Dopamine Regulation between Somatodendritic and Terminal Field Areas of Nigrostriatal and Mesoaccumbens Pathways
Salvatore, M. F., & Pruett, B. S. (2012) · PLoS ONE · doi:10.1371/journal.pone.0029867 · Cited by 62
“Thus, pharmacological agents such as antipsychotics [12,33] or neuropathological events [27,34–37]”
Silencing α-Synuclein Gene Expression Enhances Tyrosine Hydroxylase Activity in MN9D Cells
Liu, D., Jin, L., Wang, H., Zhao, H., Zhao, C., Duan, C., Lu, L., Wu, B., Yu, S., Chan, P., et al. (2008) · Neurochemical Research · doi:10.1007/s11064-008-9599-7 · Cited by 61
The interaction of α-synuclein and Tau: A molecular conspiracy in neurodegeneration?
Xu, Y., Uronen, R., & Huttunen, H. J. (2018) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2018.05.005 · Cited by 64
Lewy-like aggregation of α-synuclein reduces protein phosphatase 2A activity in vitro and in vivo
Wu, J., Lou, H., Alerte, T. N. M., Stachowski, E. K., Chen, J., Singleton, A., Hamilton, R. L., & Perez, R. G. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.01.028 · Cited by 58
“While α-Syn and the catalytic subunit of PP2A are known to interact (Peng et al., 2005), no one knows if α-Syn might also bind B subunits of PP2A to in some manner contribute to holoenzyme assembly or localization.”
BackgroundInfluentialSelf-citation
Dysregulated dopamine storage increases the vulnerability to α-synuclein in nigral neurons
Ulusoy, A., Björklund, T., Buck, K., & Kirik, D. (2012) · Neurobiology of Disease · doi:10.1016/j.nbd.2012.05.012 · Cited by 57
“…hydroxylase (TH), DA transporter (DAT) and vesicular monoamine transporter-2 (VMAT2) function, aromatic amino acid decarboxylase and tetrahydrobiopterin (co-factor essential for TH function) (Baptista et al., 2003; Lee et al., 2001; Peng et al., 2005; Perez et al., 2002; Tehranian et al., 2006).”
Background
Enhanced tyrosine hydroxylase activity induces oxidative stress, causes accumulation of autotoxic catecholamine metabolites, and augments amphetamine effects in vivo
Vecchio, L. M., Sullivan, P., Dunn, A. R., Bermejo, M. K., Fu, R., Masoud, S. T., Gregersen, E., Urs, N. M., Nazari, R., Jensen, P. H., et al. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15432 · Cited by 56
“Protein phosphatase 2A (PP2A) is the main phosphatase responsible for dephosphorylating TH and regulating its activity (Haavik et al. 1989; Peng et al. 2005).”
BackgroundInfluential
Role of Apolipoproteins and α-Synuclein in Parkinson’s Disease
Emamzadeh, F. N. (2017) · Journal of Molecular Neuroscience · doi:10.1007/s12031-017-0942-9 · Cited by 54
“leading to deactivation of TH and reduction of dopamine levels (Peng et al. 2005; Lou et al. 2010).”
Background
Exercise does not protect against MPTP-induced neurotoxicity in BDNF happloinsufficent mice
Gerecke, K. M., Jiao, Y., Pagala, V., & Smeyne, R. J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0043250 · Cited by 53
“and alpha-synuclein aggregation; both critical to the neuropathology of Parkinson’s disease [106–109].”
Background
Linking Parkinson's Disease and Melanoma: Interplay Between α‐Synuclein and Pmel17 Amyloid Formation
Dean, D. N., & Lee, J. C. (2021) · Movement Disorders · doi:10.1002/mds.28655 · Cited by 53
“α-Syn Disrupts Tyrosine Hydroxylase and/or Tyrosinase Activity The prevailing hypothesis(26,32-34,37,39) to describe the inverse correlation between α-syn expression and melanin production states that α-syn disrupts the activities of catalytic enzymes involved in melanin biosynthesis, namely, tyrosine hydroxylase (TH)…”
Background
α-Synuclein Expression in Rat Substantia Nigra Suppresses Phospholipase D2 Toxicity and Nigral Neurodegeneration
Gorbatyuk, O. S., Li, S., Nguyen, F. N., Manfredsson, F. P., Kondrikova, G., Sullivan, L. F., Meyers, C., Chen, W., Mandel, R. J., & Muzyczka, N. (2010) · Molecular Therapy · doi:10.1038/mt.2010.137 · Cited by 56
Neurons and Glia Interplay in α-Synucleinopathies
Mavroeidi, P., & Xilouri, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094994 · Cited by 55
P2X7 Receptor is Involved in Mitochondrial Dysfunction Induced by Extracellular Alpha Synuclein in Neuroblastoma SH-SY5Y Cells
Wilkaniec, A., Cieślik, M., Murawska, E., Babiec, L., Gąssowska-Dobrowolska, M., Pałasz, E., Jęśko, H. M., & Adamczyk, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21113959 · Cited by 51
Expression and Subcellular Location of Alpha-Synuclein During Mouse-Embryonic Development
Zhong, S., Luo, X. G., Chen, X.-S., Cai, Q., Liu, J., Chen, X., & Yao, Z. (2009) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-009-9473-4 · Cited by 50
“5 in the midbrain/hindbrain junction, suggesting that a-SYN may play a yet undefined role in early brain development. a-SYN is reported to regulate DA synthesis by binding to and inhibiting tyrosine hydroxylase (TH) (Peng et al. 2005; Alerte et al. 2008).”
Background
A possible pathophysiological role of tyrosine hydroxylase in Parkinson’s disease suggested by postmortem brain biochemistry: a contribution for the special 70th birthday symposium in honor of Prof. Peter Riederer
Nakashima, A., Ota, A., Kaneko, Y. S., Mori, K., Nagasaki, H., & Nagatsu, T. (2012) · Journal of Neural Transmission · doi:10.1007/s00702-012-0828-5 · Cited by 47
Advances in the development of imaging probes and aggregation inhibitors for alpha-synuclein
Xu, M., Ryan, P., Rudrawar, S., Quinn, R. J., Zhang, H., & Mellick, G. D. (2019) · Acta Pharmacologica Sinica · doi:10.1038/s41401-019-0304-y · Cited by 49
“In addition to its role in synaptic transmission, α-syn is also involved in the suppression of apoptosis [39], antioxidation [40] and even regulation of dopamine biosynthesis [41, 42].”
Background
Phosphatases of α-synuclein, LRRK2, and tau: important players in the phosphorylation-dependent pathology of Parkinsonism
Taymans, J., & Baekelandt, V. (2014) · Frontiers in Genetics · doi:10.3389/fgene.2014.00382 · Cited by 47
Expression of α-synuclein is increased in the hippocampus of rats with high levels of innate anxiety
Chiavegatto, S., Izídio, G. S., Mendes-Lana, A., Aneas, I., Freitas, T. A., Torrão, A. D. S., Conceição, I. M., Britto, L. R., & Ramos, A. (2008) · Molecular Psychiatry · doi:10.1038/mp.2008.43 · Cited by 46
RNA interference targeting α-synuclein attenuates methamphetamine-induced neurotoxicity in SH-SY5Y cells
Chen, L., Huang, E., Wang, H., Qiu, P., & Liu, C. (2013) · Brain Research · doi:10.1016/j.brainres.2013.05.016 · Cited by 44
Protein Phosphatase 2A: a Double-Faced Phosphatase of Cellular System and Its Role in Neurodegenerative Disorders
Nematullah, M., Hoda, M. N., & Khan, F. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0444-3 · Cited by 44
“rat) cells leads to enhanced PP2A activation [105].”
Background
Melatonin inhibits amphetamine-induced increase in α-synuclein and decrease in phosphorylated tyrosine hydroxylase in SK–N–SH cells
Klongpanichapak, S., Phansuwan‐Pujito, P., Ebadi, M., & Govitrapong, P. (2008) · Neuroscience Letters · doi:10.1016/j.neulet.2008.03.053 · Cited by 41
FTY720 Improves Behavior, Increases Brain Derived Neurotrophic Factor Levels and Reduces α-Synuclein Pathology in Parkinsonian GM2 +/− Mice
Vidal-Martínez, G., Najera, K., Miranda, J. D., Gil-Tommee, C., Yang, B. C., Vargas‐Medrano, J., Diaz-Pacheco, V., & Perez, R. G. (2019) · Neuroscience · doi:10.1016/j.neuroscience.2019.05.029 · Cited by 39
“…often contain Lewy Bodies, inclusions with abundant aSyn, a presynaptic protein that broadly contributes to dopamine regulation (Perez et al., 2002; Perez and Hastings, 2004; Peng et al., 2005; Tehranian et al., 2006; Porras and Perez, 2014; Benskey et al., 2016; Mor and Ischiropoulos, 2018).”
BackgroundSelf-citation
Dysregulation of external globus pallidus‐subthalamic nucleus network dynamics in parkinsonian mice during cortical slow‐wave activity and activation
Kovaleski, R. F., Callahan, J. W., Chazalon, M., Wokosin, D. L., Baufreton, J., & Bevan, M. D. (2020) · The Journal of Physiology · doi:10.1113/jp279232 · Cited by 39
“…detection of tyrosine hydroxylase (TH; 1:500 mouse anti-TH; MAB318, RRID:AB 2201528; MilliporeSigma; Charalampopoulos et al. 2005; Peng et al. 2005; 1:250 Alexa Fluor 488 donkey anti-mouse IgG; 715-545-152, RRID: AB 2313584; Jackson Immunoresearch) and expression was quantified,…”
Background
Lack of involvement of alpha-synuclein in unconditioned anxiety in mice
Peña‐Oliver, Y., Buchman, V. L., & Stephens, D. (2010) · Behavioural Brain Research · doi:10.1016/j.bbr.2010.01.049 · Cited by 39
“Alpha-synuclein down-regulates dopamine transmission by inhibiting the activity of tyrosine hydroxylase, decreasing dopamine synthesis and acting as a negative regulator of DA release (Peng et al., 2005; Perez et al., 2002).”
Co-treatment with natural HMGB1 inhibitor Glycyrrhizin exerts neuroprotection and reverses Parkinson’s disease like pathology in Zebrafish
Ren, Q., Jiang, X. J., Paudel, Y. N., Gao, X., Gao, D., Zhang, P., Sheng, W., Shang, X., Liu, K., Zhang, X., et al. (2022) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2022.115234 · Cited by 38
Alpha-synuclein overexpression increases phospho-protein phosphatase 2A levels via formation of calmodulin/Src complex
Yang, W., Wang, X., Duan, C., Lu, L., & Yang, H. (2013) · Neurochemistry International · doi:10.1016/j.neuint.2013.06.010 · Cited by 38

Authors: Peng, X. M., Tehranian, R., Dietrich, P., Stefanis, L., & Perez, R. G.
Affiliations: University of Pittsburgh (US)
Columbia University (US)
ORCID: Peng, Xiangmin M.
Dietrich, Paula
Stefanis, Leonidas
Perez, Ruth G.
Venue: Journal of Cell Science
Publisher: The Company of Biologists
Published: 2005-08-01
Volume: 118
Issue: 15
Pages: 3523-3530
ISSN: 0021-9533 (ISSN-L)
1477-9137
DOI: 10.1242/jcs.02481
OpenAlex: W2077584190
Cited by: 249
References: 52
Citations by year: 2026: 4 · 2025: 3 · 2024: 13 · 2023: 11 · 2022: 12 · 2021: 16 · 2020: 18 · 2019: 18 · 2018: 13 · 2017: 16 · 2016: 8 · 2015: 7 · 2014: 13 · 2013: 13 · 2012: 21
FWCI: 4.75
Type: journal article
Language: en
Open access: closed
Locations: Journal of Cell Science (publishedVersion)
PubMed (publishedVersion)
HighWire Press Open Archive (submittedVersion)
Funders: National Institute of Neurological Disorders and Stroke (NS42094, R01NS042094)
Topics: Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
Health Sciences › Medicine › Clinical Neurology › Deep Brain Stimulation and Movement Disorders
Keywords: alpha-synuclein, protein phosphatase 2A, tyrosine hydroxylase, tyrosine hydroxylase phosphorylation, dopamine synthesis, dopaminergic neurons, protein kinase A, protein dephosphorylation, Parkinson's disease, protein-protein interaction
MeSH terms: Animals, Cell Line, Dopamine, Gene Expression Regulation, Mice, Inbred C57BL, Phosphoprotein Phosphatases, Phosphorylation, Serine, Tyrosine 3-Monooxygenase, PC12 Cells, Okadaic Acid, Mice, Rats, Protein Phosphatase 2

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α-Synuclein activation of protein phosphatase 2A reduces tyrosine hydroxylase phosphorylation in dopaminergic cells

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