G51D α‐synuclein mutation causes a novel Parkinsonian–pyramidal syndrome

Lesage, Suzanne; Anheim, Mathieu; Letournel, Franck; Bousset, Luc; Honoré, Aurélie; Rozas, Nelly; Pieri, Laura; Madiona, Karine; Dürr, Alexandra; Melki, Ronald; Verny, Christophe; Brice, Alexis

doi:10.1002/ana.23894

Cited by 635 publications

(510 citation statements)

References 34 publications

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“…Both immunohistochemical (17,22) and proteomic studies (20) have shown that α-Syn within LBs and other different inclusions can be ubiquitinated and phosphorylated at S129 and/or at Y125 (17,22,30,31). Interestingly, exogenously prepared α-Syn fibrils are rapidly ubiquitinated and phosphorylated at S129 upon internalization in mammalian cell lines and following stereotaxic injection and uptake by neurons in mouse brain (32,33).…”

Section: Resultsmentioning

confidence: 99%

“…Despite several reports demonstrating that ubiquitinated α-Syn is also phosphorylated at its C terminus (S129 and Y125) (17,22,30,31), the interplay across these modifications has not previously been investigated. Our results demonstrate that the effect of phosphorylation at Y125 on α-Syn aggregation is dependent on the length of the poly-Ub chain.…”

Section: Discussionmentioning

confidence: 99%

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Synthetic polyubiquitinated α-Synuclein reveals important insights into the roles of the ubiquitin chain in regulating its pathophysiology

Haj‐Yahya

Fauvet

Herman-Bachinsky

et al. 2013

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

139

115

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Ubiquitination regulates, via different modes of modifications, a variety of biological processes, and aberrations in the process have been implicated in the pathogenesis of several neurodegenerative diseases. However, our ability to dissect the pathophysiological relevance of the ubiquitination code has been hampered due to the lack of methods that allow site-specific introduction of ubiquitin (Ub) chains to a specific substrate. Here, we describe chemical and semisynthetic strategies for site-specific incorporation of K48-linked di-or tetra-Ub chains onto the side chain of Lys12 of α-Synuclein (α-Syn). These advances provided unique opportunities to elucidate the role of ubiquitination and Ub chain length in regulating α-Syn stability, aggregation, phosphorylation, and clearance. In addition, we investigated the cross-talk between phosphorylation and ubiquitination, the two most common α-Syn pathological modifications identified within Lewy bodies and Parkinson disease. Our results suggest that α-Syn functions under complex regulatory mechanisms involving cross-talk among different posttranslational modifications. eukaryotes is the covalent attachment of ubiquitin (Ub) to proteins. This reversible modification, which regulates a variety of biological processes, such as protein degradation, trafficking, and DNA damage response (1, 2), involves the attachment of the C terminus of Ub mainly to the side chain of a Lys residue in a protein substrate via an isopeptide linkage. The process is catalyzed by three enzymes that act in concert: the Ub-activating enzyme (E1), the Ub-conjugating enzyme (E2), and the Ub ligase (E3). The reaction is repeated, and a second Ub is attached to an internal Lys in the previously conjugated ubiquitin. Several repeats result in the synthesis of a poly-Ub chain that can be of varying lengths and internal linkages. The presence of seven Lys residues as possible anchoring sites within Ub in addition to the N-terminal amine results in a highly complex landscape of diverse Ub bioconjugates, which accounts for the diversity of the Ub signaling (3).Research in the Ub field, which aims at understanding the ubiquitination system at the molecular level, has been hampered by the difficulties of controlling ubiquitination in the cell and challenges associated with the preparation of specific Ub conjugates in vitro. These limitations have inspired the development of novel synthetic strategies to facilitate site-specific ubiquitination of proteins (4, 5). Recent advancements in the field have enabled the synthesis of relatively large amounts of highly complex Ub conjugates of defined covalent structure and provided novel insights into the structural, biochemical, and functional consequences of protein ubiquitination, along with unique opportunities to elucidate the molecular basis of Ub signaling. For example, monoubiquitinated α-Synuclein (α-Syn) and histone H2B bearing native isopeptide bonds were prepared and used to shed light on the role of monoubiquitination in regulating α-Syn aggregation a...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Synthetic polyubiquitinated α-Synuclein reveals important insights into the roles of the ubiquitin chain in regulating its pathophysiology

Haj‐Yahya

Fauvet

Herman-Bachinsky

et al. 2013

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

139

115

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“…Mis‐sense mutations13, 36, 37, 38, 39, 40 and duplications or triplications of the SNCA gene, which encodes αS, lead to autosomal dominant early onset PD 41, 42. It has previously been shown that the formation of αS oligomers in vitro is concentration dependent,12 and ADPAINT now enables us to determine whether this dependence is reflected in cellular models that overexpress αS.…”

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confidence: 99%

Nanoscopic Characterisation of Individual Endogenous Protein Aggregates in Human Neuronal Cells

et al. 2018

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The aberrant misfolding and subsequent conversion of monomeric protein into amyloid aggregates characterises many neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. These aggregates are highly heterogeneous in structure, generally of low abundance and typically smaller than the diffraction limit of light (≈250 nm). To overcome the challenges these characteristics pose to the study of endogenous aggregates formed in cells, we have developed a method to characterise them at the nanometre scale without the need for a conjugated fluorophore. Using a combination of DNA PAINT and an amyloid‐specific aptamer, we demonstrate that this technique is able to detect and super‐resolve a range of aggregated species, including those formed by α‐synuclein and amyloid‐β. Additionally, this method enables endogenous protein aggregates within cells to be characterised. We found that neuronal cells derived from patients with Parkinson's disease contain a larger number of protein aggregates than those from healthy controls.

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“…Therefore, the identification and validation of biomarkers of PD is crucial for early diagnosis, monitoring the progression of the disease, designing clinical trials, and assessing the effectiveness of therapeutic strategies. The presence of fibrillar and aggregated forms of ␣-syn within LBs combined with the findings that genetic mutations (3)(4)(5)(6)(7) or gene duplication or triplication (8,9) promote ␣-syn aggregation and fibrillization and cause early-onset forms of PD suggest that the process of LB formation plays a central role in neurodegeneration and the pathogenesis of PD. The molecular factors that contribute to triggering ␣-syn aggregation and LB formation remain unknown.…”

mentioning

confidence: 99%

“…This approach was implemented by our group in a recent study aimed at detecting the presence of truncated forms of ␣-syn and their phosphorylated counterparts in brain extracts of a mouse model overexpressing human A30P, which shows accumulation of pS129 ␣-syn similar to that observed in human synucleinopathy patients. 3 In this study, recombinant truncated forms of ␣-syn at Y133 and D135 were used (i) to optimize the conditions for detecting the corresponding C-terminal peptides in mouse model brain extract samples, (ii) to test the specificity of newly developed antibodies targeting the alternative C termini, and (iii) to compare the propensity of the truncated forms to be phosphorylated at S129 by PLK-3 relative to the full-length protein.…”

mentioning

confidence: 99%

Alpha-synuclein Post-translational Modifications as Potential Biomarkers for Parkinson Disease and Other Synucleinopathies

Schmid

Fauvet

Moniatte

et al. 2013

Molecular & Cellular Proteomics

176

145

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The development of novel therapies against neurodegenerative disorders requires the ability to detect their early, presymptomatic manifestations in order to enable treatment before irreversible cellular damage occurs. Precocious signs indicative of neurodegeneration include characteristic changes in certain protein levels, which can be used as diagnostic biomarkers when they can be detected in fluids such as blood plasma or cerebrospinal fluid. In the case of synucleinopathies, cerebrospinal alpha-synuclein (␣-syn) has attracted great interest as a potential biomarker; however, there is ongoing debate regarding the association between cerebrospinal ␣-syn levels and neurodegeneration in Parkinson disease and synucleinopathies. Post-translational modifications (PTMs) have emerged as important determinants of ␣-syn's physiological and pathological functions. Several PTMs are enriched within Lewy bodies and exist at higher levels in ␣-synucleinopathy brains, suggesting that certain modified forms of ␣-syn might be more relevant biomarkers than the total ␣-syn levels. However, the quantification of PTMs in bodily fluids poses several challenges. This review describes the limitations of current immunoassay-based ␣-syn quantification methods and highlights how these limitations can be overcome using novel mass-spectrometrybased assays. In addition, we describe how advances in chemical synthesis, which have enabled the preparation of ␣-syn proteins that are site-specifically modified at single or multiple residues, can facilitate the development of more accurate assays for detecting and quantifying ␣-syn PTMs in health and disease. Molecular & Cellular Proteomics

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G51D α‐synuclein mutation causes a novel Parkinsonian–pyramidal syndrome

Abstract: We have identified a novel SNCA G51D mutation that causes a form of PD with unusual clinical, neuropathological, and biochemical features.

Cited by 635 publications

References 34 publications

Synthetic polyubiquitinated α-Synuclein reveals important insights into the roles of the ubiquitin chain in regulating its pathophysiology

Synthetic polyubiquitinated α-Synuclein reveals important insights into the roles of the ubiquitin chain in regulating its pathophysiology

Nanoscopic Characterisation of Individual Endogenous Protein Aggregates in Human Neuronal Cells

Alpha-synuclein Post-translational Modifications as Potential Biomarkers for Parkinson Disease and Other Synucleinopathies

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