Lrrk2 phosphorylates alpha synuclein at serine 129: Parkinson disease implications

Qing, Hong; Wong, William; McGeer, Edith G.; McGeer, Patrick L.

doi:10.1016/j.bbrc.2009.06.142

Cited by 140 publications

(120 citation statements)

References 25 publications

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“…The unphosphorylated recombinant a-syn protein was treated with casein kinase-2 (CK2), which is a serine/threonineselective protein kinase (Fujiwara et al, 2002), to generate a-syn protein phosphorylated at S129. Both unphosphorylated and phosphorylated forms of a-syn were then analyzed by western blotting using anti-a-syn monoclonal antibodies LB509 [for total a-syn (Jakes et al, 1999)], EP1536Y [for S129-phosphorylated a-syn (Fournier et al, 2009;Qing et al, 2009)], and 4D6. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Role of Ser129 phosphorylation of α-synuclein in melanoma cells

Lee

Matsuo

Cashikar

et al. 2013

Journal of Cell Science

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Summary a-Synuclein, a protein central to Parkinson's disease, is frequently expressed in melanoma tissues, but not in non-melanocytic cutaneous carcinoma and normal skin. Thus, a-synuclein is not only related to Parkinson's disease, but also to melanoma. Recently, epidemiologists reported co-occurrence of melanoma and Parkinson's disease in patients, suggesting that these diseases could share common pathogenetic components and that a-synuclein might be one of these. In Parkinson's disease, phosphorylation of a-synuclein at Ser129 plays an important role in the pathobiology. However, its role in melanoma is not known. Here, we show the biological relevance of Ser129 phosphorylation in human melanoma cells. First, we have identified an antibody that reacts with Ser129-unphosphorylated asynuclein but not with Ser129-phosphorylated a-synuclein. Using this and other antibodies to a-synuclein, we investigated the role of Ser129 phosphorylation in human melanoma SK-MEL28 and SK-MEL5 cells. Our immunofluorescence microscopy showed that the Ser129-phosphorylated form, but not the Ser129-unphosphorylated form, of a-synuclein localizes to dot-like structures at the cell surface and the extracellular space. Furthermore, immuno-electron microscopy showed that the melanoma cells release microvesicles in which Ser129-phosphorylated a-synuclein localizes to the vesicular membrane. Taken together, our studies suggest that the phosphorylation of Ser129 leads to the cell surface translocation of a-synuclein along the microtubule network and its subsequent vesicular release in melanoma cells.

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Section: Resultsmentioning

confidence: 99%

Role of Ser129 phosphorylation of α-synuclein in melanoma cells

Lee

Matsuo

Cashikar

et al. 2013

Journal of Cell Science

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“…The mechanism that causes post-translational changes of AS includes phosphorylation at residue serin (Ser)129 by kinases [118][119][120][121] (promoting fibril formation in vitro [122]), C-terminal truncation and ubiquitination [123], being a common feature in synucleinopathies [124]. In a mouse model overexpressing AS enhanced phosphatase activity reduced the phosphorylation and aggregation of AS [125], but the mechanisms for degradation of pAS are unclear.…”

Section: The Synuclein Protein Familymentioning

confidence: 99%

The role of α-synuclein in neurodegeneration — An update

Jellinger¹

2012

Translational Neuroscience

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Genetic, neuropathological and biochemical evidence implicates α-synuclein, a 140 amino acid presynaptic neuronal protein, in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. The aggregated protein inclusions mainly containing aberrant α-synuclein are widely accepted as morphological hallmarks of α-synucleinopathies, but their composition and location vary between disorders along with neuronal networks affected. α-Synuclein exists physiologically in both soluble and membran-bound states, in unstructured and α-helical conformations, respectively, while posttranslational modifications due to proteostatic deficits are involved in β-pleated aggregation resulting in formation of typical inclusions. The physiological function of α-synuclein and its role linked to neurodegeneration, however, are incompletely understood. Soluble oligomeric, not fully fibrillar α-synuclein is thought to be neurotoxic, main targets might be the synapse, axons and glia. The effects of aberrant α-synuclein include alterations of calcium homeostasis, mitochondrial dysfunction, oxidative and nitric injuries, cytoskeletal effects, and neuroinflammation. Proteasomal dysfunction might be a common mechanism in the pathogenesis of neuronal degeneration in α-synucleinopathies. However, how α-synuclein induces neurodegeneration remains elusive as its physiological function. Genome wide association studies demonstrated the important role for genetic variants of the SNCA gene encoding α-synuclein in the etiology of Parkinson's disease, possibly through effects on oxidation, mitochondria, autophagy, and lysosomal function. The neuropathology of synucleinopathies and the role of α-synuclein as a potential biomarker are briefly summarized. Although animal models provided new insights into the pathogenesis of Parkinson disease and multiple system atrophy, most of them do not adequately reproduce the cardinal features of these disorders. Emerging evidence, in addition to synergistic interactions of α-synuclein with various pathogenic proteins, suggests that prionlike induction and seeding of α-synuclein could lead to the spread of the pathology and disease progression. Intervention in the early aggregation pathway, aberrant cellular effects, or secretion of α-synuclein might be targets for neuroprotection and disease-modifying therapy.

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“…Although the domain structure of Lrrk2 is well known, the understanding of the physiological function and the impact of pathogenic mutations on the molecular mechanisms leading to PD still remain uncertain. In vitro studies demonstrated that Lrrk2 is both a functional kinase and GTPase, able to undergo autophosphorylation and perform phosphorylation of generic and putative physiological substrates (13)(14)(15). Some mutations have been shown to increase the protein's kinase activity (16 -18) and to induce cellular toxicity in vitro, leading to the hypothesis that the kinase activity contributes to neurodegeneration (18,19).…”

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confidence: 99%