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000163870 0247_ $$2ISSN$$a1460-2075
000163870 037__ $$aDZNE-2022-00557
000163870 041__ $$aEnglish
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000163870 1001_ $$aKarpinar, Damla Pinar$$b0
000163870 245__ $$aPre-fibrillar alpha-synuclein variants with impaired beta-structure increase neurotoxicity in Parkinson's disease models.
000163870 260__ $$aHoboken, NJ [u.a.]$$bWiley$$c2009
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000163870 520__ $$aThe relation of alpha-synuclein (alphaS) aggregation to Parkinson's disease (PD) has long been recognized, but the mechanism of toxicity, the pathogenic species and its molecular properties are yet to be identified. To obtain insight into the function different aggregated alphaS species have in neurotoxicity in vivo, we generated alphaS variants by a structure-based rational design. Biophysical analysis revealed that the alphaS mutants have a reduced fibrillization propensity, but form increased amounts of soluble oligomers. To assess their biological response in vivo, we studied the effects of the biophysically defined pre-fibrillar alphaS mutants after expression in tissue culture cells, in mammalian neurons and in PD model organisms, such as Caenorhabditis elegans and Drosophila melanogaster. The results show a striking correlation between alphaS aggregates with impaired beta-structure, neuronal toxicity and behavioural defects, and they establish a tight link between the biophysical properties of multimeric alphaS species and their in vivo function.
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000163870 650_7 $$2NLM Chemicals$$aalpha-Synuclein
000163870 650_2 $$2MeSH$$aAnimals
000163870 650_2 $$2MeSH$$aAnimals, Genetically Modified
000163870 650_2 $$2MeSH$$aBrain: metabolism
000163870 650_2 $$2MeSH$$aBrain: pathology
000163870 650_2 $$2MeSH$$aCaenorhabditis elegans: metabolism
000163870 650_2 $$2MeSH$$aCell Line
000163870 650_2 $$2MeSH$$aDisease Models, Animal
000163870 650_2 $$2MeSH$$aDrosophila: metabolism
000163870 650_2 $$2MeSH$$aHumans
000163870 650_2 $$2MeSH$$aMagnetic Resonance Spectroscopy
000163870 650_2 $$2MeSH$$aNeurons: metabolism
000163870 650_2 $$2MeSH$$aNeurons: pathology
000163870 650_2 $$2MeSH$$aParkinson Disease: metabolism
000163870 650_2 $$2MeSH$$aParkinson Disease: pathology
000163870 650_2 $$2MeSH$$aProtein Multimerization
000163870 650_2 $$2MeSH$$aProtein Structure, Secondary
000163870 650_2 $$2MeSH$$aRats
000163870 650_2 $$2MeSH$$aalpha-Synuclein: chemistry
000163870 650_2 $$2MeSH$$aalpha-Synuclein: genetics
000163870 650_2 $$2MeSH$$aalpha-Synuclein: metabolism
000163870 7001_ $$aBalija, Madhu Babu Gajula$$b1
000163870 7001_ $$aKügler, Sebastian$$b2
000163870 7001_ $$aOpazo, Felipe$$b3
000163870 7001_ $$0P:(DE-2719)9000418$$aRezaei-Ghaleh, Nasrollah$$b4$$udzne
000163870 7001_ $$aWender, Nora$$b5
000163870 7001_ $$aKim, Hai-Young$$b6
000163870 7001_ $$aTaschenberger, Grit$$b7
000163870 7001_ $$0P:(DE-2719)2814178$$aFalkenburger, Björn H$$b8
000163870 7001_ $$aHeise, Henrike$$b9
000163870 7001_ $$aKumar, Ashutosh$$b10
000163870 7001_ $$aRiedel, Dietmar$$b11
000163870 7001_ $$aFichtner, Lars$$b12
000163870 7001_ $$aVoigt, Aaron$$b13
000163870 7001_ $$aBraus, Gerhard H$$b14
000163870 7001_ $$aGiller, Karin$$b15
000163870 7001_ $$aBecker, Stefan$$b16
000163870 7001_ $$aHerzig, Alf$$b17
000163870 7001_ $$aBaldus, Marc$$b18
000163870 7001_ $$aJäckle, Herbert$$b19
000163870 7001_ $$aEimer, Stefan$$b20
000163870 7001_ $$aSchulz, Jörg B$$b21
000163870 7001_ $$aGriesinger, Christian$$b22
000163870 7001_ $$0P:(DE-2719)2810591$$aZweckstetter, Markus$$b23$$udzne
000163870 773__ $$0PERI:(DE-600)1467419-1$$a10.1038/emboj.2009.257$$gVol. 28, no. 20, p. 3256 - 3268$$n20$$p3256 - 3268$$tThe EMBO journal$$v28$$x0261-4189$$y2009
000163870 8564_ $$uhttps://www.embopress.org/doi/full/10.1038/emboj.2009.257
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