α-Synuclein aggregation alters tyrosine hydroxylase phosphorylation and immunoreactivity: Lessons from viral transduction of knockout mice

Alerte, Tshianda N.M.; Akinfolarin, Akinwande A.; Friedrich, Emily E.; Mader, Samantha A.; Hong, Chang-Sook; Perez, Ruth G.

doi:10.1016/j.neulet.2008.02.014

Cited by 98Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingAlzheimer's disease research and treatments

α-Synuclein aggregation alters tyrosine hydroxylase phosphorylation and immunoreactivity: Lessons from viral transduction of knockout mice

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Alerte, Tshianda N.M., Akinfolarin, Akinwande A., Friedrich, Emily E., Mader, Samantha A., Hong, Chang-Sook, Perez, Ruth G.·2008·Neuroscience Letters

DOI 10.1016/j.neulet.2008.02.014PMC PMC2440662

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Abstract

Tyrosine hydroxylase (TH), the rate limiting enzyme in catecholamine synthesis, is frequently used as a marker of dopaminergic neuronal loss in animal models of Parkinson's disease (PD). We have been exploring the normal function of the PD-related protein alpha-synuclein (alpha-Syn) with regard to dopamine synthesis. TH is activated by the phosphorylation of key seryl residues in the TH regulatory domain. Using in vitro models, our laboratory discovered that alpha-Syn inhibits TH by acting to reduce TH phosphorylation, which then reduces dopamine synthesis [X.-M. Peng, R. Tehranian, P. Dietrich, L. Stefanis, R.G. Perez, Alpha-synuclein activation of protein phosphatase 2A reduces tyrosine hydroxylase phosphorylation in dopaminergic cells, J. Cell. Sci. 118 (2005) 3523-3530; R.G. Perez, J.C. Waymire, E. Lin, J.J. Liu, F. Guo, M.J. Zigmond, A role for alpha-synuclein in the regulation of dopamine biosynthesis, J. Neurosci. 22 (2002) 3090-3099]. We recently began exploring the impact of alpha-Syn on TH in vivo, by transducing dopaminergic neurons in alpha-Syn knockout mouse (ASKO) olfactory bulb using wild type human alpha-Syn lentivirus. At 3.5-21 days after viral delivery, alpha-Syn expression was transduced primarily in periglomerular dopaminergic neurons. Cells with modest levels of alpha-Syn consistently co-labeled for Total-TH. However, cells bearing aggregated alpha-Syn, as revealed by proteinase K or Thioflavin-S treatment had significantly reduced Total-TH immunoreactivity, but high phosphoserine-TH labeling. On immunoblots, we noted that Total-TH immunoreactivity was equivalent in all conditions, although tissues with alpha-Syn aggregates again had higher phosphoserine-TH levels. This suggests that aggregated alpha-Syn is no longer able to inhibit TH. Although the reason(s) underlying reduced Total-TH immunoreactivity on tissue sections await(s) confirmation, the dopaminergic phenotype was easily verified using phosphorylation-state-specific TH antibodies. These findings have implications not only for normal alpha-Syn function in TH regulation, but also for measuring cell loss that is associated with synucleinopathy.

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Aggregation of α-synuclein potentiates TH phosphorylation and reduces total TH protein.
“Such aggregation of α-synuclein presumably potentiates TH phosphorylation and reduces total TH protein [116,122,123].”
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 [123]

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Inhibition of tyrosine hydroxylase expression in α-synuclein-transfected dopaminergic neuronal cells
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Authors: Alerte, T. N. M., Akinfolarin, A. A., Friedrich, E. E., Mader, S. A., Hong, C.-S., & Perez, R. G.
Affiliations: University of Pittsburgh (US)
Corresponding author: Perez, Ruth G.
ORCID: Akinfolarin, Akinwande A.
Friedrich, Emily E.
Perez, Ruth G.
Venue: Neuroscience Letters
Publisher: Elsevier BV
Published: 2008-04
Volume: 435
Issue: 1
Pages: 24-29
ISSN: 0304-3940 (ISSN-L)
DOI: 10.1016/j.neulet.2008.02.014
PMC: PMC2440662
OpenAlex: W2172296192
Cited by: 98
References: 42
Citations by year: 2026: 4 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 10 · 2020: 2 · 2019: 5 · 2018: 4 · 2017: 8 · 2016: 11 · 2015: 4 · 2014: 3 · 2013: 7 · 2012: 7
FWCI: 5.30
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Neuroscience Letters (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute of Neurological Disorders and Stroke (NS42094, R01NS042094)
Topics: Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords: alpha-synuclein, tyrosine hydroxylase, tyrosine hydroxylase phosphorylation, dopamine synthesis, dopaminergic neurons, Parkinson's disease, lentiviral transduction, olfactory bulb, protein aggregation, dopaminergic neuron loss, protein phosphatase 2A
MeSH terms: Animals, Cells, Cultured, Inclusion Bodies, Disease Models, Animal, Dopamine, Genetic Vectors, Humans, Immunohistochemistry, Male, Nerve Degeneration, Neurons, Olfactory Bulb, Parkinson Disease, Phosphorylation, Substantia Nigra, Transduction, Genetic, Transfection, Tyrosine 3-Monooxygenase, Down-Regulation, Lentivirus, Mice, Knockout, Mice, alpha-Synuclein

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α-Synuclein aggregation alters tyrosine hydroxylase phosphorylation and immunoreactivity: Lessons from viral transduction of knockout mice

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