Interference of alpha-synuclein with cAMP/PKA-dependent CREB signaling for tyrosine hydroxylase gene expression in SK-N-BE(2)C cells

Kim, Sa Suk; Moon, Kyung Rok; Choi, Hyun Jin

doi:10.1007/s12272-011-0518-0

Cited by 19 publications

(14 citation statements)

References 41 publications

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“…CREB binds DNA sequences with cAMP response elements (CRE), which are present in the promoter of many genes, including tyrosine hydroxylase (TH) and synapsin I [19], [20]. Studies from our laboratory and other groups have previously reported decreased TH mRNA levels in HPRT-deficient cells [4], [8].…”

Section: Resultsmentioning

confidence: 99%

HPRT-Deficiency Dysregulates cAMP-PKA Signaling and Phosphodiesterase 10A Expression: Mechanistic Insight and Potential Target for Lesch-Nyhan Disease?

2013

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Lesch-Nyhan Disease (LND) is the result of mutations in the X-linked gene encoding the purine metabolic enzyme, hypoxanthine guanine phosphoribosyl transferase (HPRT). LND gives rise to severe neurological anomalies including mental retardation, dystonia, chorea, pyramidal signs and a compulsive and aggressive behavior to self injure. The neurological phenotype in LND has been shown to reflect aberrant dopaminergic signaling in the basal ganglia, however there are little data correlating the defect in purine metabolism to the neural-related abnormalities. In the present studies, we find that HPRT-deficient neuronal cell lines have reduced CREB (cAMP response element-binding protein) expression and intracellular cyclic AMP (cAMP), which correlates with attenuated CREB-dependent transcriptional activity and a reduced phosphorylation of protein kinase A (PKA) substrates such as synapsin (p-syn I). Of interest, we found increased expression of phosphodiesterase 10A (PDE10A) in HPRT-deficient cell lines and that the PDE10 inhibitor papaverine and PDE10A siRNA restored cAMP/PKA signaling. Furthermore, reconstitution of HPRT expression in mutant cells partly increased cAMP signaling synapsin phosphorylation. In conclusion, our data show that HPRT-deficiency alters cAMP/PKA signaling pathway, which is in part due to the increased of PDE10A expression and activity. These findings suggest a mechanistic insight into the possible causes of LND and highlight PDE10A as a possible therapeutic target for this intractable neurological disease.

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Section: Resultsmentioning

confidence: 99%

HPRT-Deficiency Dysregulates cAMP-PKA Signaling and Phosphodiesterase 10A Expression: Mechanistic Insight and Potential Target for Lesch-Nyhan Disease?

2013

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“…The cAMP and Protein kinase A (PKA) signaling system may be affected at more levels by interactions with catalytic subunit beta, regulatory subunit type 2, as well as scaffolding A-kinase anchor protein 5. Such interactions may be involved in the αSN dependent attenuation of cAMP dependent TH gene expression in cells [ 69 ]. Additionally, we identified Protein kinase C epsilon, calcium/calmodulin-dependent protein kinase type 2, alpha subunit and creatine kinase thus linking αSN sensitive targets to phospholipase C and its substrate diacylglycerol, calcium regulation and bioenergetics.…”

Section: Discussionmentioning

confidence: 99%

Identification of Synaptosomal Proteins Binding to Monomeric and Oligomeric α-Synuclein

Betzer¹,

Movius

Shi

et al. 2015

PLoS ONE

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Monomeric α-synuclein (αSN) species are abundant in nerve terminals where they are hypothesized to play a physiological role related to synaptic vesicle turn-over. In Parkinson’s disease (PD) and dementia with Lewy body (DLB), αSN accumulates as aggregated soluble oligomers in terminals, axons and the somatodendritic compartment and insoluble filaments in Lewy inclusions and Lewy neurites. The autosomal dominant heritability associated to mutations in the αSN gene suggest a gain of function associated to aggregated αSN. We have conducted a proteomic screen to identify the αSN interactome in brain synaptosomes. Porcine brain synaptosomes were fractionated, solubilized in non-denaturing detergent and subjected to co-immunoprecipitation using purified recombinant human αSN monomers or oligomers as bait. The isolated αSN binding proteins were identified with LC-LTQ-orbitrap tandem mass spectrometry and quantified by peak area using Windows client application, Skyline Targeted Proteomic Environment. Data are available via ProteomeXchange with identifier PXD001462. To quantify the preferential binding an average fold increase was calculated by comparing binding to monomer and oligomer. We identified 10 proteins preferentially binding monomer, and 76 binding preferentially to oligomer and a group of 92 proteins not displaying any preferred conformation of αSN. The proteomic data were validated by immunoprecipitation in both human and porcine brain extracts using antibodies against monomer αSN interactors: Abl interactor 1, and myelin proteolipid protein, and oligomer interactors: glutamate decarboxylase 2, synapsin 1, glial fibrillary acidic protein, and VAMP-2. We demonstrate the existence of αSN conformation selective ligands and present lists of proteins, whose identity and functions will be useful for modeling normal and pathological αSN dependent processes.

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“…ASYN accumulation was found to up-regulate caveolin-1 and to down regulate several signaling pathways, upstream of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), such as extracellular signal regulated protein kinase (ERK), protein kinase C (PKC) [286,287], nuclear factor kappa B (NF-kB) [248,288] and glycogen synthase kinase 3b (GSK3b) [260]. Consequently, downregulation of CREB leads to impairment of its downstream targets, namely Bcl-2 [260] and brain-derived neurotrophic factor (BDNF) expression [289], which impairs tyrosine hydroxylase (TH) expression [290]. However, nuclear ASYN also downregulates expression of the nuclear receptor, Nurr1, and its downstream target, GDNF receptor, Ret.…”

Section: Asyn and Transcriptional Deregulationmentioning

confidence: 99%

Limelight on Alpha-Synuclein: Pathological and Mechanistic Implications in Neurodegeneration

Wales

Pinho

Lázaro

et al. 2013

Journal of Parkinson's Disease

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The pathogenesis of many neurodegenerative disorders arises in association with the misfolding and accumulation of a wide variety of proteins. Much emphasis has been placed on understanding the nature of these protein accumulations, including their composition, the process by which they are formed and the physiological impact they impose at cellular and, ultimately, organismal levels. Alpha-synuclein (ASYN) is the major component of protein inclusions known as Lewy bodies and Lewy neurites, which are the typical pathological hallmarks in disorders referred to as synucleinopathies. In addition, mutations or multiplications in the gene encoding for ASYN have also been shown to cause familial cases of PD, the most common synucleinopathy. Although the precise function of ASYN remains unclear, it appears to be involved in a vast array of cellular processes. Here, we review, in depth, a spectrum of cellular and molecular mechanisms that have been implicated in synucleinopathies. Importantly, detailed understanding of the biology/pathobiology of ASYN may enable the development of novel avenues for diagnosis and/or therapeutic intervention in synucleinopathies.The initial implication of alpha-synuclein (ASYN) in neurodegeneration arose with the identification of its presence in amyloid plaques of Alzheimer's disease (AD) patients [1]. Though ASYN was discovered half a decade prior, in the electric organ of Torpedo californica, and initially named synuclein for its ostensibly restricted cellular localizations, within synaptic nerve terminals and within the nuclear envelope [2], 1 Equal contribution.

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Interference of alpha-synuclein with cAMP/PKA-dependent CREB signaling for tyrosine hydroxylase gene expression in SK-N-BE(2)C cells

Cited by 19 publications

References 41 publications

HPRT-Deficiency Dysregulates cAMP-PKA Signaling and Phosphodiesterase 10A Expression: Mechanistic Insight and Potential Target for Lesch-Nyhan Disease?

HPRT-Deficiency Dysregulates cAMP-PKA Signaling and Phosphodiesterase 10A Expression: Mechanistic Insight and Potential Target for Lesch-Nyhan Disease?

Identification of Synaptosomal Proteins Binding to Monomeric and Oligomeric α-Synuclein

Limelight on Alpha-Synuclein: Pathological and Mechanistic Implications in Neurodegeneration

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