Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease and Dopa-Responsive Dystonia
Open accessAbstract
Nigrostriatal dopaminergic systems govern physiological functions related to locomotion, and their dysfunction leads to movement disorders, such as Parkinson’s disease and dopa-responsive dystonia (Segawa disease). Previous studies revealed that expression of the gene encoding nigrostriatal tyrosine hydroxylase (TH), a rate-limiting enzyme of dopamine biosynthesis, is reduced in Parkinson’s disease and dopa-responsive dystonia; however, the mechanism of TH depletion in these disorders remains unclear. In this article, we review the molecular mechanism underlying the neurodegeneration process in dopamine-containing neurons and focus on the novel degradation pathway of TH through the ubiquitin-proteasome system to advance our understanding of the etiology of Parkinson’s disease and dopa-responsive dystonia. We also introduce the relation of α-synuclein propagation with the loss of TH protein in Parkinson’s disease as well as anticipate therapeutic targets and early diagnosis of these diseases.
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Written from the paper’s full text.
TL;DR
This review proposes that phosphorylated tyrosine hydroxylase (TH), especially pSer40-TH, is ubiquitinated and degraded by the ubiquitin-proteasome system, contributing to loss of nigrostriatal TH protein in Parkinson’s disease and dopa-responsive dystonia. It also links α-synuclein aggregation/propagation and FABP3-mediated uptake to increased TH phosphorylation and reduced TH protein, suggesting therapeutic and early diagnostic targets.
Key findings
- Nigrostriatal TH protein is markedly reduced in PD and DRD; DRD patients show severely reduced (<3%) TH protein in the putamen, and in PD the striatal decrease in total TH protein is greater than the decrease in total enzyme activity, suggesting phosphorylation-linked loss.
- Proteasome inhibition causes accumulation of ubiquitin-positive pSer40-TH and insoluble inclusions in NGF-differentiated PC12D cells; dopamine or biopterin deficiency potentiates Ser40 phosphorylation and ubiquitination, and pSer40-TH degradation is sensitive to MG-132.
- α-Synuclein aggregation increases pSer40-TH and decreases total TH protein in cultured dopaminergic neurons; soluble α-synuclein may maintain phosphorylated TH via PP2A, whereas aggregated/filamentous α-synuclein promotes TH phosphorylation and degradation.
- FABP3 is reported critical for α-synuclein uptake into dopaminergic neurons and spreading; serum FABP3 is increased in PD, and FABP3 ligands inhibit α-synuclein oligomerization in PD mouse models, suggesting therapeutic targets.
Methods
- Narrative review; no primary experimental data or systematic search strategy described.
- Synthesizes published in vitro, animal, and human postmortem evidence on TH phosphorylation, ubiquitination/proteasomal degradation, α-synuclein, and FABP3.
- Main analysis is conceptual integration, proposing a “negative spiral” of TH phosphorylation-induced degradation in PD and DRD.
Limitations
- The paper states the molecular mechanism of onset and TH loss is not completely elucidated and that further study is needed.
- Evident: as a narrative review, it does not report a systematic literature search, quality assessment, or meta-analysis, and conclusions rely on cited studies rather than new primary data.
- Evident: many mechanistic claims are based on cell and animal models; the text notes uncertainty about why dopaminergic neurons selectively degenerate and about factors beyond α-synuclein itself.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
Statistics
Claims the paper makes
0 of 65 cited sources checked · 0 supported · 0 flagged
- Findingcitation
26S proteasomal inhibition leads to formation of insoluble inclusions of pSer40-TH in NGF-differentiated PC12D cells.
“We further revealed that 26S proteasomal inhibition leads to accumulation of TH phosphorylated at Ser40 (pSer40-TH), which are ubiquitin-positive, as well as formation of its insoluble inclusions in NGF-differentiated PC12D cells [70].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [70] Kawahata, 2009, Accumulation of phosphorylated tyrosine hydroxylase into insoluble protein aggregates by inhibition of an ubiquitin-proteasome system in PC12D cells, J. Neural Transm. source
Not checked in the free run.
- Findingcitation
Proteasomal inhibition leads to accumulation of pSer40-TH, which is ubiquitin-immunopositive, in NGF-differentiated PC12D cells.
“we previously found that proteasomal inhibition leads to accumulation of pSer40-TH, which is ubiquitin-immunopositive, in nerve growth factor (NGF)-differentiated PC12D cells [70].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [70] Kawahata, 2009, Accumulation of phosphorylated tyrosine hydroxylase into insoluble protein aggregates by inhibition of an ubiquitin-proteasome system in PC12D cells, J. Neural Transm. source
Not checked in the free run.
- Findingown data
Formation of intracellular aggregations of filamentous α-synuclein led to a decrease in total TH protein levels with increased pSer40-TH in cultured dopaminergic neurons.
“Indeed, we revealed that the formation of intracellular aggregations of filamentous α-synuclein led to a decrease in the total TH protein levels with increased pSer40-TH in cultured dopaminergic neurons (Figure 4).”
Quote in the paperSubstantial claim - Findingcitation
FABP3 is essential in MPP+-induced morphological abnormality, mitochondrial dysfunction and neurotoxicity.
“FABP3 is also essential in 1-methyl-4-phenylpyridinium (MPP+)-induced morphological abnormality, mitochondrial dysfunction and neurotoxicity [144].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [144] Kawahata, I., Bousset, L., Melki, R., and Fukunaga, K. (2019). Fatty Acid-Binding Protein 3 is Critical for alpha-Synuclein Uptake and MPP(+)-Induced Mitochondrial Dysfunction in Cultured Dopaminergic Neurons. Int. J. Mol. Sci., 20. source
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- Findingcitation
FABP3 ligand inhibits α-synuclein oligomerization in PD mouse models.
“Intriguingly, FABP3 ligand, which we have recently synthesized, inhibits α-synuclein oligomerization in PD mouse models [150,151].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [150] Matsuo, 2019, Inhibition of MPTP-induced alpha-synuclein oligomerization by fatty acid-binding protein 3 ligand in MPTP-treated mice, Neuropharmacology source
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- cites [151] Cheng, 2019, Development of FABP3 ligands that inhibit arachidonic acid-induced alpha-synuclein oligomerization, Brain Res. source
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- Premisecitation
In PD, the decrease in total TH protein level in the striatum is greater than the decrease in total TH enzyme activity.
“Mogi et al. found that a decrease in total TH protein level in the striatum was greater than that in the total enzyme activity, as assessed by enzyme immunoassay [69].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [69] Mogi, 1988, Homospecific activity (activity per enzyme protein) of tyrosine hydroxylase increases in parkinsonian brain, J. Neural Transm. source
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- Premisecitation
Recombinant human TH protein forms insoluble aggregates in the presence of tetrahydrobiopterin in vitro.
“Urano et al. reported that recombinant human TH protein forms insoluble aggregates in the presence of tetrahydrobiopterin in vitro [99].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [99] Urano, 2006, Molecular mechanism for pterin-mediated inactivation of tyrosine hydroxylase: Formation of insoluble aggregates of tyrosine hydroxylase, J. Biochem. source
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- Premisecitation
Lewy bodies and Lewy neurites are pSer40-TH-immunopositive in PD.
“Lewy bodies and Lewy neurites are pSer40-TH-immunopositive in PD [71].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [71] Kawahata, 2009, Immunohistochemical analyses of the postmortem human brains from patients with Parkinson’s disease with anti-tyrosine hydroxylase antibodies, Biog. Amines
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- Interpretationown data
Intracellular pSer40-TH insolubility indicates that pSer40-TH easily forms aggregates in living cells.
“The phenomenon of intracellular pSer40-TH insolubility unveiled the characteristics of pSer40-TH that it easily forms aggregates in living cells (Figure 2).”
Quote in the paperSubstantial claim - Premisecitation
TH protein, particularly phosphorylated TH, forms intracellular aggregates easily.
“TH protein, particularly phosphorylated TH, apparently forms intracellular aggregates easily [70,72].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [70] Kawahata, 2009, Accumulation of phosphorylated tyrosine hydroxylase into insoluble protein aggregates by inhibition of an ubiquitin-proteasome system in PC12D cells, J. Neural Transm. source
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- cites [72] Baumann, 2016, Tyrosine Hydroxylase Binding to Phospholipid Membranes Prompts Its Amyloid Aggregation and Compromises Bilayer Integrity, Sci. Rep. source
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- Premisecitation
Soluble α-synuclein physically interacts with TH and maintains the level of phosphorylated TH in a PP2A-dependent manner.
“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]”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [114] Peng, 2005, Alpha-synuclein activation of protein phosphatase 2A reduces tyrosine hydroxylase phosphorylation in dopaminergic cells, J. Cell Sci. source
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- cites [115] Lou, 2010, Serine 129 phosphorylation reduces the ability of alpha-synuclein to regulate tyrosine hydroxylase and protein phosphatase 2A in vitro and in vivo, J. Biol. Chem. source
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- cites [116] Perez, 2002, A role for alpha-synuclein in the regulation of dopamine biosynthesis, J. Neurosci. source
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- Interpretationcitation
Reduction of proteasomal activity in PD supports the accumulation of pSer40-TH to form inclusion bodies in PD patients.
“Insight into the reduction of proteasomal activity in PD [94,95,96] further supports the evidence of the accumulation of pSer40-TH to form inclusion bodies in PD patients [71].”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [94] McNaught, 2001, Proteasomal function is impaired in substantia nigra in Parkinson’s disease, Neurosci. Lett. source
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- cites [95] McNaught, 2001, Failure of the ubiquitin-proteasome system in Parkinson’s disease, Nat. Rev. Neurosci. source
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- cites [96] McNaught, 2003, Proteolytic stress: A unifying concept for the etiopathogenesis of Parkinson’s disease, Ann. Neurol. source
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- cites [71] Kawahata, 2009, Immunohistochemical analyses of the postmortem human brains from patients with Parkinson’s disease with anti-tyrosine hydroxylase antibodies, Biog. Amines
Not checked in the free run.
- Interpretationreasoning
These observations support the novel pathway of proteasomal degradation of TH protein.
“These observations support the novel pathway of proteasomal degradation of TH protein.”
Quote in the paperSubstantial claim - Premisecitation
Reduction of TH immunoreactivity is observed in the midbrain and striatum of 6-pyruvoyl-tetrahydrobiopterin synthase-null and sepiapterin reductase-null mice, which are mouse models of tetrahydrobiopterin biosynthesis dysfunction.
“The reduction of TH immunoreactivity can be observed in the midbrain and striatum of 6-pyruvoyl-tetrahydrobiopterin synthase-null and sepiapterin reductase-null mice, which are mouse models of tetrahydrobiopterin biosynthesis dysfunction [75,76].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [75] Urano, 2001, Catecholamines and serotonin are differently regulated by tetrahydrobiopterin. A study from 6-pyruvoyltetrahydropterin synthase knockout mice, J. Biol. Chem. source
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- cites [76] Takazawa, 2008, A brain-specific decrease of the tyrosine hydroxylase protein in sepiapterin reductase-null mice--as a mouse model for Parkinson’s disease, Biochem. Biophys. Res. Commun. source
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- Premisecitation
Phosphorylation of the N-terminal TH domain causes proteasomal degradation.
“A publication by Nakashima et al. also showed the proteasomal degradation of the TH protein and evidence that phosphorylation of the N-terminal TH domain causes proteasomal degradation [100,101].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [100] Nakashima, 2011, Phosphorylation of the N-terminal portion of tyrosine hydroxylase triggers proteasomal digestion of the enzyme, Biochem. Biophys. Res. Commun. source
Not checked in the free run.
- cites [101] Nakashima, 2016, Inhibition of deubiquitinating activity of USP14 decreases tyrosine hydroxylase phosphorylated at Ser19 in PC12D cells, Biochem. Biophys. Res. Commun. source
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- Premisecitation
Short-term inhibition of proteasome increases the accumulation of ubiquitinated TH protein in PC12 cells and brainstem neurons.
“Carbajosa et al. also reported that short-term inhibition of proteasome increases the accumulation of ubiquitinated TH protein in PC12 cells and brainstem neurons [102]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [102] Carbajosa, N.A., Corradi, G., Verrilli, M.A., Guil, M.J., Vatta, M.S., and Gironacci, M.M. (2015). Tyrosine hydroxylase is short-term regulated by the ubiquitin-proteasome system in PC12 cells and hypothalamic and brainstem neurons from spontaneously hypertensive rats: Possible implications in hypertension. PLoS ONE, 10. source
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- Interpretationcitation
Factors other than α-synuclein itself may be associated with neuronal degeneration of dopaminergic neurons.
“factors other than α-synuclein itself may be associated with the neuronal degeneration of dopaminergic neurons.”
Quote in the paperSubstantial claim - Premisecitation
Expression of the gene encoding nigrostriatal tyrosine hydroxylase (TH) is reduced in Parkinson's disease and dopa-responsive dystonia.
“Previous studies revealed that expression of the gene encoding nigrostriatal tyrosine hydroxylase (TH), a rate-limiting enzyme of dopamine biosynthesis, is reduced in Parkinson’s disease and dopa-responsive dystonia”
- Also stated in: § 1. Introduction · plain
“the loss of nigrostriatal tyrosine hydroxylase (TH) protein is distinctive in PD and DRD.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [5] Furukawa, 1999, Striatal biopterin and tyrosine hydroxylase protein reduction in dopa-responsive dystonia, Neurology source
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- cites [6] Furukawa, 2002, Brain biopterin and tyrosine hydroxylase in asymptomatic dopa-responsive dystonia, Ann. Neurol. source
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- Also stated in: § 1. Introduction · plain
- Interpretationcitation
Upregulation of TH phosphorylation, which compensates decreased dopamine level, is linked to the reduction of nigrostriatal TH protein in PD.
“This result suggests that upregulation of TH phosphorylation, which compensates decreased dopamine level, is linked to the reduction of nigrostriatal TH protein in PD.”
Quote in the paperSubstantial claim - Premisecitation
DRD patients have severely reduced (<3%) TH protein levels in the putamen.
“DRD patients have severely reduced (<3%) TH protein levels in the putamen [5,6].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [5] Furukawa, 1999, Striatal biopterin and tyrosine hydroxylase protein reduction in dopa-responsive dystonia, Neurology source
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- cites [6] Furukawa, 2002, Brain biopterin and tyrosine hydroxylase in asymptomatic dopa-responsive dystonia, Ann. Neurol. source
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- Premisecitation
Dopamine and biopterin deficiencies lead to reduced total TH protein, caused by degradation of pSer40-TH.
“dopamine and biopterin deficiencies lead to reduced total TH protein, which is caused by the degradation of pSer40-TH [74].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [74] Kawahata, 2015, Dopamine or biopterin deficiency potentiates phosphorylation at (40)Ser and ubiquitination of tyrosine hydroxylase to be degraded by the ubiquitin proteasome system, Biochem. Biophys. Res. Commun. source
Not checked in the free run.
- Interpretationreasoning
Phosphorylated TH protein is ubiquitinated to be degraded by the ubiquitin-proteasome system.
“Altogether, these data strongly suggest that phosphorylated TH protein is ubiquitinated to be degraded by the ubiquitin-proteasome system (Figure 2).”
Quote in the paperSubstantial claim - Interpretationcitation
TH, especially phosphorylated TH, is ubiquitinated, resulting in its degradation by the ubiquitin-proteasome system.
“indicating that TH, especially phosphorylated TH, is ubiquitinated, resulting in its degradation by the ubiquitin-proteasome system.”
Quote in the paperSubstantial claim - Premisecitation
Failure of the ubiquitin-proteasome system is implicated in the pathogenesis of both sporadic and familial PD.
“Failure of the ubiquitin-proteasome system is implicated in the pathogenesis of both sporadic and familial PD [22,23,24,94,95,96].”
Quote in the paperNot a substantial claim0 of 6 sources checked- cites [22] Kitada, 1998, Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism, Nature source
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- cites [23] Hattori, 1998, Point mutations (Thr240Arg and Gln311Stop) [correction of Thr240Arg and Ala311Stop] in the Parkin gene, Biochem. Biophys. Res. Commun. source
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- cites [24] Shimura, 2000, Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase, Nat. Genet. source
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- cites [94] McNaught, 2001, Proteasomal function is impaired in substantia nigra in Parkinson’s disease, Neurosci. Lett. source
Not checked in the free run.
- cites [95] McNaught, 2001, Failure of the ubiquitin-proteasome system in Parkinson’s disease, Nat. Rev. Neurosci. source
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- cites [96] McNaught, 2003, Proteolytic stress: A unifying concept for the etiopathogenesis of Parkinson’s disease, Ann. Neurol. source
Not checked in the free run.
- Interpretationreasoning
Formation of insoluble inclusions of pSer40-TH further reduces cytoplasmic operable TH.
“The formation of insoluble inclusions of pSer40-TH further reduces cytoplasmic operable TH.”
Quote in the paperSubstantial claim - Interpretationown data
FABP3 is a potential therapeutic target in synucleinopathies that can act by preventing α-synuclein uptake into dopaminergic neurons.
“These data suggest that FABP3 is a potential therapeutic target in synucleinopathies that can act by preventing α-synuclein uptake into dopaminergic neurons.”
Quote in the paperSubstantial claim - Premisecitation
Accumulation of propagated α-synuclein results in synucleinopathies, including PD, DLB, and multiple system atrophy.
“Accumulation of propagated α-synuclein results in synucleinopathies, including PD, DLB, and multiple system atrophy [137].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [137] Wong, 2017, alpha-synuclein toxicity in neurodegeneration: Mechanism and therapeutic strategies, Nat. Med. source
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- Interpretationreasoning
α-Synuclein uptake into living neuronal cells is critical for the pathogenesis of synucleinopathies.
“Thus, α-synuclein uptake into living neuronal cells is critical for the pathogenesis of synucleinopathies.”
Quote in the paperSubstantial claim - Premisecitation
Serum FABP3 level is increased in PD.
“Intriguingly, serum FABP3 level is increased in PD [152].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [152] Teunissen, 2011, Brain-specific fatty acid-binding protein is elevated in serum of patients with dementia-related diseases, Eur. J. Neurol. source
Not checked in the free run.
- Interpretationreasoning
The negative spiral mechanism of TH phosphorylation-induced degradation is involved in the loss of nigrostriatal TH protein in PD and DRD.
“We suggest that the negative spiral mechanism of TH phosphorylation-induced degradation is involved in the loss of nigrostriatal TH protein in PD and DRD (Figure 5).”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from cultured cells and animal models about TH degradation and α-synuclein aggregation reflect the pathogenic process in human PD and DRD.
- Interpretationreasoning
The mechanism of ubiquitin-proteasome-linked dopaminergic pathogenesis might help explain the dopaminergic neuron-selective loss of TH protein in PD and DRD.
“The mechanism of ubiquitin-proteasome-linked dopaminergic pathogenesis might help explain the dopaminergic neuron-selective loss of TH protein in PD and DRD.”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from cultured cells and animal models about TH degradation and α-synuclein aggregation reflect the pathogenic process in human PD and DRD.
- Interpretationown data
FABP3-targeting ligands are potential therapeutic candidates for synucleinopathies.
“These data suggest that FABP3-targeting ligands are potential therapeutic candidates for synucleinopathies.”
Quote in the paperSubstantial claim - Interpretationreasoning
α-Synuclein-induced abnormal upregulation of TH phosphorylation, combined with reduction of gene transcription by aging and aging-related disorders, accelerates pSer40-TH degradation to reduce total TH protein.
“The α-synuclein-induced abnormal upregulation of TH phosphorylation, combined with the reduction of gene transcription by aging and aging-related disorders [126,127,128,129], results in the acceleration of pSer40-TH degradation to reduce total TH protein (Figure 3).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [126] Collier, 2007, Aging-related changes in the nigrostriatal dopamine system and the response to MPTP in nonhuman primates: Diminished compensatory mechanisms as a prelude to parkinsonism, Neurobiol. Dis. source
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- cites [127] Burhans, 2007, DNA replication stress, genome instability and aging, Nucleic Acids Res. source
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- cites [128] Anisimova, 2018, Protein synthesis and quality control in aging, Aging (Albany NY) source
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- cites [129] Rodriguez, 2015, Parkinson’s disease as a result of aging, Aging Cell source
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- Rests on an assumption: α-Synuclein aggregation is a cause, rather than a consequence, of increased TH phosphorylation and reduced total TH in PD.
- Premisecitation
α-Synuclein activates stress-related protein kinases to potentiate TH phosphorylation at serine 40.
“α-Synuclein activates stress-related protein kinases to potentiate TH phosphorylation at serine 40, suggesting the possible mechanism of pSer40-TH elevation by α-synuclein aggregation [52,124,125].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [52] Dunkley, 2004, Tyrosine hydroxylase phosphorylation: Regulation and consequences, J. Neurochem. source
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- cites [124] Toska, 2002, Regulation of tyrosine hydroxylase by stress-activated protein kinases, J. Neurochem. source
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- cites [125] Klegeris, 2008, Alpha-synuclein activates stress signaling protein kinases in THP-1 cells and microglia, Neurobiol. Aging source
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- Interpretationreasoning
The ubiquitin-proteasome system participates in the degradation of phosphorylated TH.
“We conclude that the ubiquitin-proteasome system participates in the degradation of phosphorylated TH.”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from cultured cells and animal models about TH degradation and α-synuclein aggregation reflect the pathogenic process in human PD and DRD.
- May combine two claims. 16
- Classified as probably not a substantial claim. 2
May combine two claims.
FindingcitationFABP3 is critical for α-synuclein uptake into dopaminergic neurons and enhances α-synuclein spreading.
“Very recently, we showed that fatty acid-binding protein 3 (FABP3) is critical for α-synuclein uptake into dopaminergic neurons [144] and enhancement of α-synuclein spreading [145].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [144] Kawahata, I., Bousset, L., Melki, R., and Fukunaga, K. (2019). Fatty Acid-Binding Protein 3 is Critical for alpha-Synuclein Uptake and MPP(+)-Induced Mitochondrial Dysfunction in Cultured Dopaminergic Neurons. Int. J. Mol. Sci., 20. source
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- cites [145] Yabuki, Y., Matsuo, K., Kawahata, I., Fukui, N., Mizobata, T., Kawata, Y., Owada, Y., Shioda, N., and Fukunaga, K. (2020). Fatty Acid Binding Protein 3 Enhances the Spreading and Toxicity of alpha-Synuclein in Mouse Brain. Int. J. Mol. Sci., 21. source
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May combine two claims.
FindingcitationProteasomal inhibition results in TH aggregation, whereas choline acetyltransferase does not show such aggregations.
“Interestingly, proteasomal inhibition results in TH aggregation, whereas choline acetyltransferase does not show such aggregations [70].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [70] Kawahata, 2009, Accumulation of phosphorylated tyrosine hydroxylase into insoluble protein aggregates by inhibition of an ubiquitin-proteasome system in PC12D cells, J. Neural Transm. source
Not checked in the free run.
May combine two claims.
InterpretationreasoningLack of dopamine accelerates proteasomal degradation of TH and its phosphorylation through PKA activation, resulting in loss of TH protein and a negative spiral of TH depletion.
“Moreover, the lack of dopamine accelerates the proteasomal degradation of TH and its phosphorylation through PKA activation, resulting in the loss of TH protein and the negative spiral of TH depletion (Figure 3).”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationDopamine-modified α-synuclein blocks chaperone-mediated autophagy, which induces abnormal intracellular accumulation of α-synuclein in PD.
“dopamine-modified α-synuclein blocks chaperone-mediated autophagy [109,110], which induces abnormal intracellular accumulation α-synuclein in PD [120].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [109] Cuervo, 2004, Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy, Science source
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- cites [110] Vogiatzi, 2008, Wild type alpha-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells, J. Biol. Chem. source
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- cites [120] Talloczy, 2008, Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy, J. Clin. Investig.
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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitationα-Synuclein is degraded by proteasomes, and phosphorylated α-synuclein is ubiquitinated in α-synucleinopathy lesions, indicating that the ubiquitin-proteasome system degrades phosphorylated synuclein.
“α-Synuclein is degraded by proteasomes [106,107], and phosphorylated α-synuclein is ubiquitinated in α-synucleinopathy lesions [108], indicating that the ubiquitin-proteasome system degrades phosphorylated synuclein.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [106] Bennett, 1999, Degradation of alpha-synuclein by proteasome, J. Biol. Chem. source
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- cites [107] Giasson, 2003, Are ubiquitination pathways central to Parkinson’s disease?, Cell source
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- cites [108] Hasegawa, 2002, Phosphorylated alpha-synuclein is ubiquitinated in alpha-synucleinopathy lesions, J. Biol. Chem. source
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May combine two claims.
PremisecitationHuman recombinant TH protein is ubiquitinated and degraded in the reticulocyte lysate system.
“Døskeland and Flatmark reported that human recombinant TH protein is ubiquitinated and degraded in the reticulocyte lysate system [98].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [98] Flatmark, 2002, Ubiquitination of soluble and membrane-bound tyrosine hydroxylase and degradation of the soluble form, Eur. J. Biochem. source
Not checked in the free run.
May combine two claims.
PremisecitationKnockout of dopamine transporter decreases dopamine content in terminals of dopaminergic neurons, accompanied by elevation of pSer40-TH and reduction of total TH protein.
“Salvatore et al. further revealed that knockout of dopamine transporter decreased dopamine content in the terminals of dopaminergic neurons, and this phenomenon was accompanied by the elevation of pSer40-TH and reduction of total TH protein [103].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [103] Salvatore, 2016, Regulation of Tyrosine Hydroxylase Expression and Phosphorylation in Dopamine Transporter-Deficient Mice, ACS Chem. Neurosci. source
Not checked in the free run.
May combine two claims.
PremisecitationParkinsonian brains have very low levels of TH mRNAs in the substantia nigra compared with control brains, but no significant differences are found between schizophrenic and normal brains.
“Ichinose et al. previously showed that Parkinsonian brains had very low levels of TH mRNAs in the substantia nigra compared with control brains, but no significant differences were found between schizophrenic and normal brains [68].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [68] Ichinose, 1994, Quantification of mRNA of tyrosine hydroxylase and aromatic L-amino acid decarboxylase in the substantia nigra in Parkinson’s disease and schizophrenia, J. Neural Transm. Park. Dis. Dement. Sect. source
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Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationreasoningα-Synuclein monomer prevents excessive phosphorylation of TH by activating PP2A.
“which suggests the possibility that α-synuclein monomer prevents excessive phosphorylation of TH by activating PP2A.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationpSer40-TH degradation is sensitive to MG-132, a 26S proteasome inhibitor, indicating ubiquitin-proteasome system-mediated degradation.
“This pSer40-TH degradation was sensitive to MG-132, a 26S proteasome inhibitor [74], indicating a ubiquitin-proteasome system-mediated degradation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [74] Kawahata, 2015, Dopamine or biopterin deficiency potentiates phosphorylation at (40)Ser and ubiquitination of tyrosine hydroxylase to be degraded by the ubiquitin proteasome system, Biochem. Biophys. Res. Commun. source
Not checked in the free run.
May combine two claims.
PremisecitationThe dopamine- or biopterin-deficient state, corresponding to PD or DRD, facilitates TH phosphorylation and leads to reduction of total TH level in cultured cells.
“the dopamine- or biopterin-deficient state, which corresponds to PD or DRD, respectively, facilitates TH phosphorylation and leads to reduction of the total TH level in cultured cells [73,74].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [73] Kawahata, 2009, Long-term up-regulation of the level of phosphorylated tyrosine hydroxylase by depletion of dopamine or biopterin, Neurosci. Res. source
Not checked in the free run.
- cites [74] Kawahata, 2015, Dopamine or biopterin deficiency potentiates phosphorylation at (40)Ser and ubiquitination of tyrosine hydroxylase to be degraded by the ubiquitin proteasome system, Biochem. Biophys. Res. Commun. source
Not checked in the free run.
May combine two claims.
InterpretationreasoningTH protein levels in nigrostriatal dopaminergic neurons are markedly decreased in both PD and DRD, but not in schizophrenia.
“These results suggest that TH protein levels in the nigrostriatal dopaminergic neurons are markedly decreased in both PD and DRD, but not in schizophrenia.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationOverexpression of wild-type or mutant human α-synuclein caused by the TH promoter did not result in formation of pathological inclusions nor alter behavior and sensitivity to MPTP in C57BL/6 mice.
“Because the overexpression of wild-type or mutant human α-synuclein caused by the TH promoter did not result in the formation of pathological inclusions nor alter the behavior and sensitivity to 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) in C57BL/6 mice [117,118,119]”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [117] Matsuoka, 2001, Lack of nigral pathology in transgenic mice expressing human alpha-synuclein driven by the tyrosine hydroxylase promoter, Neurobiol. Dis. source
Not checked in the free run.
- cites [118] Kahle, 2001, Sensitivity to MPTP is not increased in Parkinson’s disease-associated mutant alpha-synuclein transgenic mice, J. Neurochem. source
Not checked in the free run.
- cites [119] Richfield, 2002, Behavioral and neurochemical effects of wild-type and mutated human alpha-synuclein in transgenic mice, Exp. Neurol. source
Not checked in the free run.
May combine two claims.
InterpretationcitationFailure of the ubiquitin-proteasome system in the substantia nigra in PD impairs degradation of α-synuclein, which facilitates formation of filamentous inclusions.
“the failure of the ubiquitin-proteasome system in the substantia nigra in PD [94] presumably impairs the degradation of α-synuclein, which facilitates the formation of filamentous inclusions.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [94] McNaught, 2001, Proteasomal function is impaired in substantia nigra in Parkinson’s disease, Neurosci. Lett. source
Not checked in the free run.
- Rests on an assumption: Reduced proteasomal activity in PD is sufficient to impair degradation of α-synuclein and TH in vivo.
May combine two claims.
Interpretationown dataAggregation 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].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [116] Perez, 2002, A role for alpha-synuclein in the regulation of dopamine biosynthesis, J. Neurosci. source
Not checked in the free run.
- cites [122] Perez, 2004, Could a loss of alpha-synuclein function put dopaminergic neurons at risk?, J. Neurochem. source
Not checked in the free run.
- cites [123] Alerte, 2008, Alpha-synuclein aggregation alters tyrosine hydroxylase phosphorylation and immunoreactivity: Lessons from viral transduction of knockout mice, Neurosci. Lett. source
Not checked in the free run.
- Rests on an assumption: α-Synuclein aggregation is a cause, rather than a consequence, of increased TH phosphorylation and reduced total TH in PD.
May combine two claims.
PremisecitationPlasma α-synuclein level in PD is higher than in healthy controls, indicating possible reduction of protein degradation rate.
“Plasma α-synuclein level in PD is higher than that in healthy controls [121], indicating possible reduction of protein degradation rate.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [121] Ng, 2019, Plasma alpha-synuclein detected by single molecule array is increased in PD, Ann. Clin. Transl. Neurol. source
Not checked in the free run.
May combine two claims.
InterpretationreasoningAggregation of propagated α-synuclein alters TH phosphorylation, accompanied by proteasomal degradation of pSer40-TH to decrease total TH protein.
“the aggregation of propagated α-synuclein alters TH phosphorylation, which is accompanied by the proteasomal degradation of pSer40-TH to decrease total TH protein (Figure 4).”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from cultured cells and animal models about TH degradation and α-synuclein aggregation reflect the pathogenic process in human PD and DRD.
The paper relies on this without support.
Findings from cultured cells and animal models about TH degradation and α-synuclein aggregation reflect the pathogenic process in human PD and DRD.
“We suggest that the negative spiral mechanism of TH phosphorylation-induced degradation is involved in the loss of nigrostriatal TH protein in PD and DRD (Figure 5).”
“The mechanism of ubiquitin-proteasome-linked dopaminergic pathogenesis might help explain the dopaminergic neuron-selective loss of TH protein in PD and DRD.”
The paper relies on this without support.
Reduced proteasomal activity in PD is sufficient to impair degradation of α-synuclein and TH in vivo.
“Insight into the reduction of proteasomal activity in PD [94,95,96] further supports the evidence of the accumulation of pSer40-TH to form inclusion bodies in PD patients [71].”
“the failure of the ubiquitin-proteasome system in the substantia nigra in PD [94] presumably impairs the degradation of α-synuclein, which facilitates the formation of filamentous inclusions.”
The paper relies on this without support.
α-Synuclein aggregation is a cause, rather than a consequence, of increased TH phosphorylation and reduced total TH in PD.
“Such aggregation of α-synuclein presumably potentiates TH phosphorylation and reduces total TH protein [116,122,123].”
“The α-synuclein-induced abnormal upregulation of TH phosphorylation, combined with the reduction of gene transcription by aging and aging-related disorders [126,127,128,129], results in the acceleration of pSer40-TH degradation to reduce total TH protein (Figure 3).”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
DA synthesis is limited by the rate-limiting enzyme TH, and motor symptoms of PD emerge when TH levels drop below a particular threshold.
“DA synthesis is limited by the rate-limiting enzyme TH, and motor symptoms of PD emerge when TH levels drop below a particular threshold [28,29].”
From Neuroprotective Effects of Bifidobacterium breve CCFM1067 in MPTP-Induced Mouse Models of Parkinson’s Disease (2022) · cites this paper as [29]
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Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- Kawahata, 2009, Immunohistochemical analyses of the postmortem human brains from patients with Parkinson’s disease with anti-tyrosine hydroxylase antibodies, Biog. Amines, 23, 1
Cited by
Sorted by citations
Li, T., Chu, C., Yu, L., Zhai, Q., Wang, S., Zhao, J., Zhang, H., Chen, W., & Tian, F. (2022) · Nutrients · doi:10.3390/nu14214678 · Cited by 76 · see citing works
- Authors
- Kawahata, I., & Fukunaga, K.
- Affiliations
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
- Tohoku University (JP)
- Corresponding author
- Fukunaga, Kohji
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2020-05-27
- Volume
- 21
- Issue
- 11
- Pages
- 3779
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC7312529
- OpenAlex
- W3028609772
- Semantic Scholar
- eef735e8cc969dd7670d50701567c5d08fc2dccf
- Cited by
- 71
- References
- 170
- Citations by year
- 2026: 5 · 2025: 16 · 2024: 13 · 2023: 20 · 2022: 8 · 2021: 8 · 2019: 1
- FWCI
- 1.01
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Japan Agency for Medical Research and Development (JP19dm0107071, JP18dm0107071)
- Fujita Health University
- Japan Society for the Promotion of Science (19K07097)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- tyrosine hydroxylase, ubiquitin-proteasome system, Parkinson's disease, dopa-responsive dystonia, Segawa disease, nigrostriatal dopaminergic neurons, protein degradation, dopamine synthesis, alpha-synuclein propagation, neurodegeneration, therapeutic target, early diagnosis
- MeSH terms
- Animals, Humans, Parkinson Disease, Tyrosine 3-Monooxygenase, Dystonic Disorders, Ubiquitin, Proteasome Endopeptidase Complex, Proteolysis
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