Alpha‐synuclein inhibits aromatic amino acid decarboxylase activity in dopaminergic cells

Tehranian, Roya; Montoya, Susana E.; Laar, Amber D. Van; Hastings, Teresa G.; Perez, Ruth G.

doi:10.1111/j.1471-4159.2006.04146.x

Cited by 102 publications

(79 citation statements)

References 65 publications

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“…Equal aliquots of cell extracts were then used for co-IP for TH using a pan-TH antibody or for 14-3-3 using a pan-14-3-3 antibody. A representative autoradiographic image confirms 32 P signal of TH at 60 kDa in the TH co-IP and also in the parallel 14-3-3 co-IP, confirming that 14-3-3 binds to phosphorylated TH in midbrain-derived MN9D neuronal cells. Molecular weights (M r ), determined from prestained standards, are shown on the left.…”

Section: Multiple 14-3-3 Isoforms Are Present In Similar Relative Amosupporting

confidence: 63%

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14-3-3ζ Contributes to Tyrosine Hydroxylase Activity in MN9D Cells

Wang

Lou

Pedersen

et al. 2009

Journal of Biological Chemistry

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The 14-3-3 proteins stimulate the activation of tyrosine hydroxylase (TH), the rate-limiting catecholamine biosynthetic enzyme. To explore if particular endogenous 14-3-3 isoforms specifically affected TH activity and dopamine synthesis, we utilized rodent nigrostriatal tissues and midbrain-derived MN9D dopaminergic cells. Extracts from ventral midbrain and MN9D cells contained similar pools of 14-3-3 mRNAs, with 14-3-3 being relatively abundant in both. Protein levels of 14-3-3 were also abundant. [32 P]Orthophosphate labeling of MN9D cells, followed by co-immunoprecipitation with pan-TH and pan-14-3-3 antibodies brought down similar amounts of phosphorylated TH in each, confirming that 14-3-3-bound phosphorylated TH in our cells. Co-immunoprecipitation of striatal tissues with a pan-TH antibody precipitated 14-3-3 but not another potential TH regulatory isoform, 14-3-3. In whole cell extracts from MN9D cells after 14-3-3 small interfering RNA treatments, we found that 14-3-3 knockdown significantly reduced TH activity and dopamine synthesis whereas knockdown of 14-3-3 had no effect. 14-3-3 was found co-localized on mitochondria with TH, and its knockdown by small interfering RNA reduced TH phosphorylation and TH activity in the mitochondrial pool. Together the data support a role for 14-3-3 as an endogenous activator of TH in midbrain dopaminergic neurons and furthermore, identify mitochondria as a potential novel site for dopamine synthesis, with implications for Parkinson disease.

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Section: Multiple 14-3-3 Isoforms Are Present In Similar Relative Amosupporting

confidence: 63%

“…A. Heller and L. Won, University of Chicago) express abundant TH, synthesize DA, and also quantally release DA (28 -30). Low-passage cells were grown on TPP plates (LPS, Rochester, NY) in Dulbecco's modified Eagle's medium (D5648; Sigma) and 10% fetal bovine serum (Hyclone, Logan, UT) at 37°C as previously described (28,31,32).…”

Section: Methodsmentioning

confidence: 99%

14-3-3ζ Contributes to Tyrosine Hydroxylase Activity in MN9D Cells

Wang

Lou

Pedersen

et al. 2009

Journal of Biological Chemistry

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“…4C), suggesting that DJ-1 stimulates TH activity without causing modification of TH. It has been reported that ␣-synuclein was associated with DDC and inhibited DDC activity in dopaminergic cells (23). Because DJ-1 inhibits aggregation of ␣-synuclein (16), it is interesting that DJ-1 and ␣-synuclein mutually antagonize their functions in dopamine synthesis.…”

Section: Discussionmentioning

confidence: 99%

“…Activities of Tyrosine Hydroxylase and L-Dopa Decarboxylase in Cells-TH and DDC activities in cells were measured according to the published method using HPLC (16,23). The HPLC system and column used were AKTA explorer 10 S/100 (GE Healthcare), COSMOSIL Cholester Waters (4.6 ϫ 150 mm, Nacalai Tesque, Kyoto, Japan), and the buffer used was a buffer containing 50 mM potassium phosphate (pH 2.6), 0.1 mM EDTA, 0.2 mM heptane sulfonic acid, and 10% methanol.…”

Section: Parkinson Disease (Pd)mentioning

confidence: 99%

Oxidative Status of DJ-1-dependent Activation of Dopamine Synthesis through Interaction of Tyrosine Hydroxylase and 4-Dihydroxy-l-phenylalanine (l-DOPA) Decarboxylase with DJ-1

Ishikawa

Taira

Niki

et al. 2009

Journal of Biological Chemistry

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Parkinson disease (PD) is caused by loss of dopamine, which is synthesized from tyrosine by two enzymes, tyrosine hydroxylase (TH) and 4-dihydroxy-L-phenylalanine decarboxylase (DDC).DJ-1 is a causative gene for the familial form of PD, but little is known about the roles of DJ-1 in dopamine synthesis. In this study, we found that DJ-1 directly bound to TH and DDC and positively regulated their activities in human dopaminergic cells. Mutants of DJ-1 found in PD patients, including heterozygous mutants, lost their activity and worked as dominant-negative forms toward wild-type DJ-1. When cells were treated with H 2 O 2 , 6-hydroxydopamine, or 1-methyl-4-phenylpyridinium, changes in activities of TH and DDC accompanied by oxidation of cysteine 106 of DJ-1 occurred. It was found that DJ-1 possessing Cys-106 with SH and SOH forms was active and that DJ-1 possessing Cys-106 with SO 2 H and SO 3 H forms was inactive in terms of stimulation of TH and DDC activities. These findings indicate an essential role of DJ-1 in dopamine synthesis and contribution of DJ-1 to the sporadic form of PD. Parkinson disease (PD)2 is a neurodegenerative disease that occurs by reduction of the dopamine level through dopaminergic cell death in the substantia nigra. Genetic and environmental factors are thought to be triggers for the onset of PD, but the precise molecular mechanisms are still not known. Dopamine is synthesized by the following two steps: tyrosine is converted to L-DOPA by tyrosine hydroxylase (TH) and then L-DOPA is converted to dopamine by L-dopa decarboxylase (DDC). TH is therefore a key enzyme for dopamine synthesis and is used as a marker for dopaminergic neurons.DJ-1 was first identified by our group as a novel candidate of the oncogene that transformed mouse NIH3T3 cells in cooperation with activated ras (1). Deletion and point (L166P) mutations of DJ-1 have been shown to be responsible for onset of familial Parkinson disease, PARK7 (2), and other homozygous and heterozygous mutations of DJ-1 have been identified in patients with familial or sporadic Parkinson disease (3-6). DJ-1 is a multifunctional protein and plays roles in transcriptional regulation and anti-oxidative stress function, and loss of its functions is thought to lead to the onset of Parkinson disease and cancer. DJ-1 has three cysteine residues at positions 46, 53, and 106 (Cys-46, Cys-53, and Cys-106, respectively), and these cysteine residues are oxidized after cells receive oxidative stress, resulting in scavenging of reactive oxidative species (7-12). Although DJ-1 does not directly bind to DNA, DI-1 acts as a co-activator to activate various transcription factors, including the androgen receptor and p53 tumor suppressor, PSF and Nrf2, by sequestering their inhibitory factors (13-18). The anti-oxidative stress function of DJ-1 is therefore thought to be carried out both by self-oxidation of cysteine residues and by activation of redox-related genes.It has been reported that PSF, a transcription repressor, binds to the promoter region of the TH gene...

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“…Overexpression of a-syn in transfected DA and pheochromocytomic cell lines also reduces the activity of L-aromatic AADC, an enzyme which helps in the conversion of L-DOPA to dopamine, thereby reducing dopamine levels [70]. We can infer that one of the effects of a-syn is to regulate dopamine homeostasis by directly affecting the enzymes involved in the dopamine biosynthesis pathway.…”

Section: Somatic Monoamine Neurotransmission and Amyloid Diseasesmentioning

confidence: 94%

Effect of amyloids on the vesicular machinery: implications for somatic neurotransmission

Das

Pandit

Maiti

2015

Phil. Trans. R. Soc. B

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Certain neurodegenerative diseases are thought to be initiated by the aggregation of amyloidogenic proteins. However, the mechanism underlying toxicity remains obscure. Most of the suggested mechanisms are generic in nature and do not directly explain the neuron-type specific lesions observed in many of these diseases. Some recent reports suggest that the toxic aggregates impair the synaptic vesicular machinery. This may lead to an understanding of the neuron-type specificity observed in these diseases. A disruption of the vesicular machinery can also be deleterious for extra-synaptic, especially somatic, neurotransmission (common in serotonergic and dopaminergic systems which are specifically affected in Alzheimer's disease (AD) and Parkinson's disease (PD), respectively), though this relationship has remained unexplored. In this review, we discuss amyloid-induced damage to the neurotransmitter vesicular machinery, with an eye on the possible implications for somatic exocytosis. We argue that the larger size of the system, and the availability of multi-photon microscopy techniques for directly visualizing monoamines, make the somatic exocytosis machinery a more tractable model for understanding the effect of amyloids on all types of vesicular neurotransmission. Indeed, exploring this neglected connection may not just be important, it may be a more fruitful route for understanding AD and PD.

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Alpha‐synuclein inhibits aromatic amino acid decarboxylase activity in dopaminergic cells

Cited by 102 publications

References 65 publications

14-3-3ζ Contributes to Tyrosine Hydroxylase Activity in MN9D Cells

14-3-3ζ Contributes to Tyrosine Hydroxylase Activity in MN9D Cells

Oxidative Status of DJ-1-dependent Activation of Dopamine Synthesis through Interaction of Tyrosine Hydroxylase and 4-Dihydroxy-l-phenylalanine (l-DOPA) Decarboxylase with DJ-1

Effect of amyloids on the vesicular machinery: implications for somatic neurotransmission

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