Sumoylation inhibits α-synuclein aggregation and toxicity

Krumova, Petranka; Meulmeester, Erik; Garrido, M.; Tirard, Marilyn; Hsiao, He-Hsuan; Bossis, Guillaume; Urlaub, Henning; Zweckstetter, Markus; Kügler, Sebastian; Melchior, Frauke; Bähr, Mathias; Weishaupt, Jochen H.

doi:10.1083/jcb.201010117

Cited by 217 publications

(217 citation statements)

References 57 publications

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“…Alternatively, posttranslational chemical modifications might explain the difference between MSA and PD inocula. Ubiquitination, phosphorylation, nitrosylation, and sumoylation of α-synuclein have all been reported to play a role in α-synuclein toxicity (47)(48)(49)(50).…”

Section: The Incubation Time For the Tgm83mentioning

confidence: 99%

Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism

Prusiner

Woerman

Mordes

et al. 2015

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

677

689

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Prions are proteins that adopt alternative conformations that become self-propagating; the PrPSc prion causes the rare human disorder Creutzfeldt–Jakob disease (CJD). We report here that multiple system atrophy (MSA) is caused by a different human prion composed of the α-synuclein protein. MSA is a slowly evolving disorder characterized by progressive loss of autonomic nervous system function and often signs of parkinsonism; the neuropathological hallmark of MSA is glial cytoplasmic inclusions consisting of filaments of α-synuclein. To determine whether human α-synuclein forms prions, we examined 14 human brain homogenates for transmission to cultured human embryonic kidney (HEK) cells expressing full-length, mutant human α-synuclein fused to yellow fluorescent protein (α-syn140*A53T–YFP) and TgM83+/− mice expressing α-synuclein (A53T). The TgM83+/− mice that were hemizygous for the mutant transgene did not develop spontaneous illness; in contrast, the TgM83+/+ mice that were homozygous developed neurological dysfunction. Brain extracts from 14 MSA cases all transmitted neurodegeneration to TgM83+/− mice after incubation periods of ∼120 d, which was accompanied by deposition of α-synuclein within neuronal cell bodies and axons. All of the MSA extracts also induced aggregation of α-syn*A53T–YFP in cultured cells, whereas none of six Parkinson’s disease (PD) extracts or a control sample did so. Our findings argue that MSA is caused by a unique strain of α-synuclein prions, which is different from the putative prions causing PD and from those causing spontaneous neurodegeneration in TgM83+/+ mice. Remarkably, α-synuclein is the first new human prion to be identified, to our knowledge, since the discovery a half century ago that CJD was transmissible.

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Section: The Incubation Time For the Tgm83mentioning

confidence: 99%

Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism

Prusiner

Woerman

Mordes

et al. 2015

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

677

689

View full text Add to dashboard Cite

show abstract

“…Presumably, α-synuclein prion strains represent different conformers, but currently we must entertain the possibility that a posttranslational chemical modification distinguishes one strain from another. Notably, ubiquitination, phosphorylation, nitrosylation, and sumoylation have all been reported to be covalently bound to α-synuclein (49)(50)(51)(52).…”

Section: Discussionmentioning

confidence: 99%

Propagation of prions causing synucleinopathies in cultured cells

Woerman

Stöhr

Aoyagi

et al. 2015

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

212

233

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Increasingly, evidence argues that many neurodegenerative diseases, including progressive supranuclear palsy (PSP), are caused by prions, which are alternatively folded proteins undergoing selfpropagation. In earlier studies, PSP prions were detected by infecting human embryonic kidney (HEK) cells expressing a tau fragment [TauRD(LM)] fused to yellow fluorescent protein (YFP). Here, we report on an improved bioassay using selective precipitation of tau prions from human PSP brain homogenates before infection of the HEK cells. Tau prions were measured by counting the number of cells with TauRD(LM)-YFP aggregates using confocal fluorescence microscopy. In parallel studies, we fused α-synuclein to YFP to bioassay α-synuclein prions in the brains of patients who died of multiple system atrophy (MSA). Previously, MSA prion detection required ∼120 d for transmission into transgenic mice, whereas our cultured cell assay needed only 4 d. Variation in MSA prion levels in four different brain regions from three patients provided evidence for three different MSA prion strains. Attempts to demonstrate α-synuclein prions in brain homogenates from Parkinson's disease patients were unsuccessful, identifying an important biological difference between the two synucleinopathies. Partial purification of tau and α-synuclein prions facilitated measuring the levels of these protein pathogens in human brains. Our studies should facilitate investigations of the pathogenesis of both tau and α-synuclein prion disorders as well as help decipher the basic biology of those prions that attack the CNS.

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“…14,42 It has been reported that sumoylation can modulate the clustering or cooperative binding of proteins. [22][23][24][25] Our evidence suggest a similar mechanism for the control of condensin clustering as excess sumoylation (smt4D) results in pericentric condensin declustering (Fig. 6).…”

Section: 38mentioning

confidence: 83%

“…It has been found that sumoylation can keep proteins from aggregating or clustering. [22][23][24][25] Sumoylation sites have been found on Top2, cohesin, and condensin. 19 Previously, we have shown that condensin clusters in the pericentromere.…”

Section: Smt4 Aids Condensin Clustering In the Pericentromerementioning

confidence: 99%

The SUMO deconjugating peptidase Smt4 contributes to the mechanism required for transition from sister chromatid arm cohesion to sister chromatid pericentromere separation

2015

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T he pericentromere chromatin protrudes orthogonally from the sistersister chromosome arm axis. Pericentric protrusions are organized in a series of loops with the centromere at the apex, maximizing its ability to interact with stochastically growing and shortening kinetochore microtubules. Each pericentromere loop is »50 kb in size and is organized further into secondary loops that are displaced from the primary spindle axis. Cohesin and condensin are integral to mechanisms of loop formation and generating resistance to outward forces from kinesin motors and anti-parallel spindle microtubules. A major unanswered question is how the boundary between chromosome arms and the pericentromere is established and maintained. We used sister chromatid separation and dynamics of LacO arrays distal to the pericentromere to address this issue. Perturbation of chromatin spring components results in 2 distinct phenotypes. In cohesin and condensin mutants sister pericentric LacO arrays separate a defined distance independent of spindle length. In the absence of Smt4, a peptidase that removes SUMO modifications from proteins, pericentric LacO arrays separate in proportion to spindle length increase. Deletion of Smt4, unlike depletion of cohesin and condensin, causes stretching of both proximal and distal pericentromere LacO arrays. The data suggest that the sumoylation state of chromatin topology adjusters, including cohesin, condensin, and topoisomerase II in the pericentromere, contribute to chromatin spring properties as well as the sister cohesion boundary.

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Sumoylation inhibits α-synuclein aggregation and toxicity

Abstract: Sumoylation of α-synuclein decreases its rate of aggregation and its deleterious effects in vitro and in vivo.

Cited by 217 publications

References 57 publications

Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism

Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism

Propagation of prions causing synucleinopathies in cultured cells

The SUMO deconjugating peptidase Smt4 contributes to the mechanism required for transition from sister chromatid arm cohesion to sister chromatid pericentromere separation

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