Efficient Modification of Alpha-Synuclein Serine 129 by Protein Kinase CK1 Requires Phosphorylation of Tyrosine 125 as a Priming Event

Kosten, Jonas; Binolfi, Andrés; Stuiver, Marchel; Verzini, Silvia; Theillet, François‐Xavier; Bekei, Beata; Rossum, Marleen van; Selenko, Philipp

doi:10.1021/cn5002254

Cited by 60 publications

(61 citation statements)

References 36 publications

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“…The physiological concentration of α-synuclein in neuronal synapses is estimated to be about 50 μM (27,28), a concentration of protein that can be studied by NMR spectroscopy (27,(29)(30)(31)(32). We therefore used this technique to probe potential interactions between α-synuclein and squalamine in the absence of lipids and to characterize the displacement of the protein from lipid membranes by squalamine, as suggested by the CD experiments.…”

Section: Resultsmentioning

confidence: 99%

A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity

Perni

Galvagnion

Maltsev

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

265

369

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The self-assembly of α-synuclein is closely associated with Parkinson’s disease and related syndromes. We show that squalamine, a natural product with known anticancer and antiviral activity, dramatically affects α-synuclein aggregation in vitro and in vivo. We elucidate the mechanism of action of squalamine by investigating its interaction with lipid vesicles, which are known to stimulate nucleation, and find that this compound displaces α-synuclein from the surfaces of such vesicles, thereby blocking the first steps in its aggregation process. We also show that squalamine almost completely suppresses the toxicity of α-synuclein oligomers in human neuroblastoma cells by inhibiting their interactions with lipid membranes. We further examine the effects of squalamine in a Caenorhabditis elegans strain overexpressing α-synuclein, observing a dramatic reduction of α-synuclein aggregation and an almost complete elimination of muscle paralysis. These findings suggest that squalamine could be a means of therapeutic intervention in Parkinson’s disease and related conditions.

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Section: Resultsmentioning

confidence: 99%

A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity

Perni

Galvagnion

Maltsev

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

265

369

View full text Add to dashboard Cite

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“…It is often observed that phosphates are lost during extract preparation or during mass spectrometry processing and therefore, such sites are often not reliable. Such clusters often use one specific phosphorylation seed generated by a priming kinase, which is then recognized by secondary kinases that hyper-phosphorylated the cluster (Kosten et al, 2014). Using this stringent strategy, several phosphorylation sites that have been reported previously are not found in our data.…”

Section: Discussionmentioning

confidence: 58%

Phosphorylation of Argonaute proteins affects mRNA binding and is essential for micro RNA ‐guided gene silencing in vivo

et al. 2017

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Argonaute proteins associate with microRNAs and are key components of gene silencing pathways. With such a pivotal role, these proteins represent ideal targets for regulatory post-translational modifications. Using quantitative mass spectrometry, we find that a C-terminal serine/threonine cluster is phosphorylated at five different residues in human and In human, hyper-phosphorylation does not affect microRNA binding, localization, or cleavage activity of Ago2. However, mRNA binding is strongly affected. Strikingly, on Ago2 mutants that cannot bind microRNAs or mRNAs, the cluster remains unphosphorylated indicating a role at late stages of gene silencing. In, the phosphorylation of the conserved cluster of ALG-1 is essential for microRNA function Furthermore, a single point mutation within the cluster is sufficient to phenocopy the loss of its complete phosphorylation. Interestingly, this mutant retains its capacity to produce and bind microRNAs and represses expression when artificially tethered to an mRNA Altogether, our data suggest that the phosphorylation state of the serine/threonine cluster is important for Argonaute-mRNA interactions.

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“…In addition, C-terminal methionine sulfoxides impair Y125 phosphorylation by the major tyrosine kinase Fyn [83]. As phosphorylated Y125 primes the efficient modification of S129 by CK [129], reduction in Y125 phosphorylation is likely to also diminish modifications of S129. This would support the presence of an age- and disease-dependent decline in α-syn phosphorylation in models and patients of PD [127].…”

Section: Structure Changes To α-Synuclein That Induce Oligomerisationmentioning

confidence: 99%

Post translational changes to α-synuclein control iron and dopamine trafficking; a concept for neuron vulnerability in Parkinson’s disease

Duce

Wong

Durham

et al. 2017

Mol Neurodegeneration

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Parkinson’s disease is a multifactorial neurodegenerative disorder, the aetiology of which remains elusive. The primary clinical feature of progressively impaired motor control is caused by a loss of midbrain substantia nigra dopamine neurons that have a high α-synuclein (α-syn) and iron content. α-Syn is a neuronal protein that is highly modified post-translationally and central to the Lewy body neuropathology of the disease. This review provides an overview of findings on the role post translational modifications to α-syn have in membrane binding and intracellular vesicle trafficking. Furthermore, we propose a concept in which acetylation and phosphorylation of α-syn modulate endocytic import of iron and vesicle transport of dopamine during normal physiology. Disregulated phosphorylation and oxidation of α-syn mediate iron and dopamine dependent oxidative stress through impaired cellular location and increase propensity for α-syn aggregation. The proposition highlights a connection between α-syn, iron and dopamine, three pathological components associated with disease progression in sporadic Parkinson’s disease.

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Efficient Modification of Alpha-Synuclein Serine 129 by Protein Kinase CK1 Requires Phosphorylation of Tyrosine 125 as a Priming Event

Cited by 60 publications

References 36 publications

A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity

A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity

Phosphorylation of Argonaute proteins affects mRNA binding and is essential for micro RNA ‐guided gene silencing in vivo

Post translational changes to α-synuclein control iron and dopamine trafficking; a concept for neuron vulnerability in Parkinson’s disease

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