α-Synuclein Binds to Tau and Stimulates the Protein Kinase A-catalyzed Tau Phosphorylation of Serine Residues 262 and 356

Jensen, Poul Henning; Hager, Henrik; Nielsen, Morten S.; Højrup, Peter; Gliemann, Jørgen; Jakes, Ross

doi:10.1074/jbc.274.36.25481

Cited by 351 publications

(320 citation statements)

References 46 publications

(59 reference statements)

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“…In addition, we found that mimicking αS phosphorylation increased the number of inclusions per cell. NMR spectroscopy suggests that the enhanced aggregation is due to a direct binding of Rab8a to the C-terminus of αS that has been implicated in interactions with a variety of protein partners (Burre et al, 2010;De Genst et al, 2010;Jensen et al, 1999Jensen et al, , 2000Kawamata et al, 2001;Kim et al, 2002;Yap et al, 2011). Thus, our study provides a link between physiological αS interactions and pathogenic aggregation.…”

Section: Discussionmentioning

confidence: 78%

α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner

Yin¹,

Fonseca²,

Eisbach³

et al. 2014

Neurobiology of Disease

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Alpha-synuclein (αS) misfolding is associated with Parkinson's disease (PD) but little is known about the mechanisms underlying αS toxicity. Increasing evidence suggests that defects in membrane transport play an important role in neuronal dysfunction. Here we demonstrate that the GTPase Rab8a interacts with αS in rodent brain. NMR spectroscopy reveals that the C-terminus of αS binds to the functionally important switch region as well as the C-terminal tail of Rab8a. In line with a direct Rab8a/αS interaction, Rab8a enhanced αS aggregation and reduced αS-induced cellular toxicity. In addition, Rab8 -the Drosophila ortholog of Rab8a -ameliorated αS-oligomer specific locomotor impairment and neuron loss in fruit flies. In support of the pathogenic relevance of the αS-Rab8a interaction, phosphorylation of αS at S129 enhanced binding to Rab8a, increased formation of insoluble αS aggregates and reduced cellular toxicity. Our study provides novel mechanistic insights into the interplay of the GTPase Rab8a and αS cytotoxicity, and underscores the therapeutic potential of targeting this interaction.

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Section: Discussionmentioning

confidence: 78%

α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner

Yin¹,

Fonseca²,

Eisbach³

et al. 2014

Neurobiology of Disease

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“…These data identify both PKA and GSK-3 as potential therapeutic targets for AD and other tauopathies that are characterized by neurofibrillary degeneration associated with the abnormal hyperphosphorylation of tau. It is interesting to note that 14-3-3 and ␣-synuclein, both of which stimulate PKA activity (61,62), are colocalized with neurofibrillary tangles in AD brain (63).…”

Section: Discussionmentioning

confidence: 99%

Tau Becomes a More Favorable Substrate for GSK-3 When It Is Prephosphorylated by PKA in Rat Brain

Liu

Zhang

et al. 2004

Journal of Biological Chemistry

176

117

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Microtubule-associated protein tau is abnormally hyperphosphorylated in Alzheimer's disease (AD) and other tauopathies and is believed to lead to neurodegeneration in this family of diseases. Here we show that infusion of forskolin, a specific cAMP-dependent protein kinase A (PKA) activator, into the lateral ventricle of brain in adult rats induced activation of PKA by severalfold and concurrently enhanced the phosphorylation of tau at Ser-214, Ser-198, Ser-199, and or Ser-202 (Tau-1 site) and Ser-396 and or Ser-404 (PHF-1 site), which are among the major abnormally hyperphosphorylated sites seen in AD. PKA activation positively correlated to the extent of tau phosphorylation at these sites. Infusion of forskolin together with PKA inhibitor or glycogen synthase kinase-3 (GSK-3) inhibitor revealed that the phosphorylation of tau at Ser-214 was catalyzed by PKA and that the phosphorylation at both the Tau-1 and the PHF-1 sites is induced by basal level of GSK-3, because forskolin activated PKA and not GSK-3 and inhibition of the latter inhibited the phosphorylation at Tau-1 and PHF-1 sites. Inhibition of cdc2, cdk5, or MAPK had no significant effect on the forskolin-induced hyperphosphorylation of tau. Forskolin inhibited spatial memory in a dose-dependent manner in the absence but not in the presence of R p -adenosine 3 ,5 -cyclic monophosphorothioate triethyl ammonium salt, a PKA inhibitor. These results demonstrate for the first time that phosphorylation of tau by PKA primes it for phosphorylation by GSK-3 at the Tau-1 and the PHF-1 sites and that an associated loss in spatial memory is inhibited by inhibition of the hyperphosphorylation of tau. These data provide a novel mechanism of the hyperphosphorylation of tau and identify both PKA and GSK-3 as promising therapeutic targets for AD and other tauopathies.

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“…In addition, -synuclein, as a chaperone, has been reported to interact with many other proteins, including 14-3-3, ERK1/2, parkin, etc. [32][33][34][35][36][37] . However, some of these findings remain controversial.…”

Section: Introductionmentioning

confidence: 99%

RNA interference mediated silencing of α-synuclein in MN9D cells and its effects on cell viability

et al. 2008

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ObjectiveTo silence the expression of -synuclein in MN9D dopaminergic cells using vector mediated RNA interference (RNAi) and examined its effects on cell proliferation and viability. Methods We identified two 19-nucleotide stretches within the coding region of the -synuclein gene and designed three sets of oligonucleotides to generate doublestranded (ds) oligos. The ds oligos were inserted into the pENTR TM /H1/TO vector and transfected into MN9D dopaminergic cells. -Synuclein expression was detected by RT-PCR, real-time PCR, immunocytochemistry staining and Western blot. In addition, we measured cell proliferation using growth curves and cell viability by 3-(4, 5)-dimethylthiahiazo (-z-y1)-3, 5-diphenytetrazoliumromide (MTT). Results The mRNA and protein levels of -synuclein gene were significantly down-regulated in pSH2/ -SYN-transfected cells compared with control MN9D and pSH/CON-transfected MN9D cells, while pSH1/ -SYNtransfected cells showed no significant difference. Silencing -synuclein expression does not affect cell proliferation but may decrease cell viability. Conclusion Our results demonstrated pSH2/ -SYN is an effective small interfering RNA (siRNA) sequence and potent silencing of mouse -synuclein expression in MN9D cells by vector-based RNAi, which provides the tools for studying the normal function of -synuclein and examining its role in Parkinson's disease (PD) pathogenesis.-Synuclein may be important for the viability of MN9D cells, and loss of -synuclein may induce cell injury directly or indirectly.

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α-Synuclein Binds to Tau and Stimulates the Protein Kinase A-catalyzed Tau Phosphorylation of Serine Residues 262 and 356

Cited by 351 publications

References 46 publications

α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner

α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner

Tau Becomes a More Favorable Substrate for GSK-3 When It Is Prephosphorylated by PKA in Rat Brain

RNA interference mediated silencing of α-synuclein in MN9D cells and its effects on cell viability

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