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α-Synuclein activation of protein phosphatase 2A reduces tyrosine hydroxylase phosphorylation in dopaminergic cells
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 in the soluble form physically interacts with TH and maintains the level of phosphorylated TH in a PP2A-dependent manner [114,115,116]”
From Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease and Dopa-Responsive Dystonia (2020) · cites this paper as [114]
Citations
Cites
Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal
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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).”
BackgroundCeramide activates heterotrimeric protein phosphatase 2A
Dobrowsky, R. T., Kamibayashi, C., Mumby, M. C., & Hannun, Y. A. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)82288-8 · Cited by 666 · cited 2×
“An active PP2A enzyme consists of a heterotrimer of the structural A subunit, a catalytic C subunit, and a regulatory B subunit (Dobrowsky et al., 1993).”
BackgroundProtein serine/threonine phosphatases: structure, regulation, and functions in cell growth
Mumby, M. C., & Walter, G. (1993) · Physiological Reviews · doi:10.1152/physrev.1993.73.4.673 · Cited by 661 · cited 2×
“The A and C subunits are ubiquitously expressed (Mayer et al., 1991) and form the catalytic complex (PP2A/C), which interacts with at least three different families of regulatory B subunits, as well as with certain tumor antigens (Mumby and Walter, 1993).”
BackgroundA Role for α-Synuclein in the Regulation of Dopamine Biosynthesis
Perez, R. G., Waymire, J. C., Lin, E., Liu, J. J., Guo, F., & Zigmond, M. J. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-08-03090.2002 · Cited by 598 · cited 8×
“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-citationα-Synuclein Shares Physical and Functional Homology with 14-3-3 Proteins
Ostrerova, N., Petrucelli, L., Farrer, M. J., Mehta, N., Choi, P., Hardy, J., & Wolozin, B. L. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-14-05782.1999 · Cited by 560 · cited 5×
“…protein 14-3-3 (Ostrerova et al., 1999), which binds to and regulates the activity of many cellular proteins. α-Syn interacts with and affects the activity of the enzymes phospholipase D (Ahn et al., 2002), protein kinase C and the extracellular regulated kinases (ERK) (Ostrerova et al., 1999).”
BackgroundInfluentialTyrosine hydroxylase phosphorylation: Regulation and consequences
Dunkley, P. R., Bobrovskaya, L., Graham, M. E., Von Nagy‐Felsobuki, E. I., & Dickson, P. W. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02797.x · Cited by 455 · cited 3×
“Since it is well-documented that Ser40 dephosphorylation occurs almost exclusively by PP2A (Berresheim and Kuhn, 1994; Dunkley et al., 2004; Haavik et al., 1989; Leal et al., 2002) our findings indicate that (1) TH Ser40 is dephosphorylated by PP2A in dopaminergic cells, and (2) the Ser40 residue on TH remains accessi…”
BackgroundJenco, J. M., Rawlingson, A., Daniels, B., & Morris, A. J. (1998) · Biochemistry · doi:10.1021/bi972776r · Cited by 431 · cited 2×
“…kinase mediating Ser40 phosphorylation and because α-Syn is so strongly implicated in enzymatic inhibition, e.g. ERK2, PLD2, TH (Iwata et al., 2001; Jenco et al., 1998; Perez et al., 2002) we first hypothesized that the reduction in TH Ser40 phosphorylation was probably occurring by α-Syn…”
BackgroundPerez, R. G., Soriano, S., Hayes, J. D., Ostaszewski, B. L., Xia, W., Selkoe, D. J., Chen, X., Stokin, G. B., & Koo, E. H. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.27.18851 · Cited by 387 · cited 1×
“Cell lysates prepared in 1% NP40 buffer containing protease inhibitors were sonicated for ∼5 seconds and particulates were eliminated by centrifugation at 15,000 g for 10 minute at 4°C as previously described (Perez et al., 1999).”
MethodSelf-citationMcCright, B., Rivers, A. M., Audlin, S., & Virshup, D. M. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.36.22081 · Cited by 382 · cited 2×
“…there is evidence that B subunits are associated with targeting the PP2A/C catalytic complexes to various intracellular sites such as microtubules (McCright et al., 1996; Sontag et al., 1995) and mitochondria (Ruvolo et al., 2002) suggesting that PP2A complexes are actively trafficked by their…”
BackgroundIchimura, T., Isobe, T., Okuyama, T., Takahashi, N., Araki, K., Kuwano, R., & Takahashi, Y. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.19.7084 · Cited by 339 · cited 4×
“It is known that 14-3-3 can activate TH (Ichimura et al., 1988) by 14-3-3 binding first to TH Ser19 then to TH Ser40 (Kleppe et al., 2001).”
BackgroundInfluential
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Sonne, J. H. (2013) · UKnowledge (University of Kentucky) · Cited by 3
Vecchio, L. M., Bermejo, M. K., Dunn, A. R., Milenkovic, M., Urs, N. M., Ramsey, A. J., Miller, G. W., & Salahpour, A. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/188318 · Cited by 3
“Both in vitro and in vivo studies have demonstrated that alpha-synuclein has the capacity to negatively regulate the activity of TH (Perez et al., 2002; Perez and Hastings, 2004; Peng et al., 2005; Park et al., 2007; Alerte et al., 2008; Liu et al., 2008; Farrell et al., 2014).”
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Differential expression of alpha-synuclein in the hippocampus of SHR and SLA16 isogenic rat strains
Oliveira, R. D. B., Anselmi, M., Marchette, R. C. N., Roversi, K., Fadanni, G. P., de Carvalho, L. M., Damasceno, S., Heinrich, I. A., Leal, R. B., Cavalli, J., et al. (2023) · Behavioural Brain Research · doi:10.1016/j.bbr.2023.114835 · Cited by 2
MicroRNAs as biomarkers in alcohol use disorder: from diagnostics to therapy. Review of literature
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Alpha-Synuclein and the Immune Response in Parkinson’s Disease
Roodveldt, C., Labrador‐Garrido, A., Izquierdo, G., & Pozo, D. (2011) · InTech eBooks · doi:10.5772/17417 · Cited by 3
“…Guillermo Izquierdo2 and David Pozo1 1CABIMER-Andalusian Center for Molecular Biology & Regenerative Medicine CSIC-University of Seville-UPO-Junta de Andalucía, Seville 2 Clinical Neurosciences Management Unit, Virgen Macarena University Hospital, University of Seville Medical School, Seville Spain”
Bečanović, K., de Donno, M. V., Sousa, V. C., Tedroff, J., & Svenningsson, P. (2020) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.119.264754 · Cited by 2
“…neurons in PD. Interestingly, a-synuclein has been shown to interact with TH and to repress TH activity, not only by inhibiting phosphorylation at Ser40 of TH but also by stimulating protein phosphatase 2A activity, resulting in decreased dopamine synthesis (Perez et al., 2002; Peng et al., 2005b).”
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“In dopaminergic cells, alpha-synuclein has also been a shown to function as an indirect down regulator for dopamine production via an interaction with protein phosphatase 2A.(23)”
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Dopamine-Induced α-Synuclein Oligomers
Rekas, A., Cappai, R., Curtain, C. C., & Pham, C. L. L. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-394431-3.00027-4 · Cited by 1
Dopamine and Early Onset Parkinson’s Disease
Wize, K., Kozubski, W. P., & Dorszewska, J. (2018) · InTech eBooks · doi:10.5772/intechopen.80400 · Cited by 1
“Moreover, ASN can decrease the activity of tyrosine hydroxylase and thus regulates the production of DA and control its levels [75].”
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Lomeli-Lepe, A. K., López‐Pérez, S. J., Castañeda‐Cabral, J. L., & Ureña‐Guerrero, M. E. (2024) · Molecular Biology Reports · doi:10.1007/s11033-024-09935-2 · Cited by 2
“Previous evidence has indicated that α-syn overexpression leads to reduced TH content in the SN [13 , 14], with the involvement of Ser40, whose phosphorylation significantly contributes to TH acti - vation and dopamine synthesis [15 , 16 ].”
Creating a protein-protein interaction network for alpha-synuclein
Könn, M. (2012) · Universitätsbibliothek der FU Berlin Hochschulschriftenstelle u. Dokumentenserver · doi:10.17169/refubium-7491 · Cited by 1
Shah, M. (2014) · Universitätsbibliothek der FU Berlin Hochschulschriftenstelle u. Dokumentenserver · doi:10.17169/refubium-17133 · Cited by 1
Enfermedad de Parkinson: Modificaciones oxidativas y su rol en la toxicidad de α-sinucleína
Giménez, E. (2022) · El Servicio de Difusión de la Creación Intelectual (National University of La Plata) · doi:10.35537/10915/138140 · Cited by 1
Parkinson’s Disease-Related Protein, a-Synuclein, in Malignant Melanoma
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Dopaminergic Dysfunction in Experimental Hepatic Encephalopathy
Suárez, I., Bodega, G., & Fernández, B. (2012) · InTech eBooks · doi:10.5772/29078
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Metadata
- Authors
- Peng, X. M., Tehranian, R., Dietrich, P., Stefanis, L., & Perez, R. G.
- Affiliations
- University of Pittsburgh (US)
- Columbia University (US)
- 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
- 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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