The effects of the novel A53E alpha-synuclein mutation on its oligomerization and aggregation
Lázaro, Diana F. (Universitätsmedizin Göttingen)
Dias, Mariana Castro (Universitätsmedizin Göttingen)
Carija, Anita (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Navarro, Susanna (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Madaleno, Carolina Silva (Universidade Nova de Lisboa. Centro de Estudos de Doenças Crónicas)
Tenreiro, Sandra (Universidade Nova de Lisboa. Centro de Estudos de Doenças Crónicas)
Ventura, Salvador (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Outeiro, Tiago Fleming (Max-Planck-Gesellschaft)

Date:	2016
Abstract:	α-synuclein (aSyn) is associated with both sporadic and familial forms of Parkinson's disease (PD), the second most common neurodegenerative disorder after Alzheimer's disease. In particular, multiplications and point mutations in the gene encoding for aSyn cause familial forms of PD. Moreover, the accumulation of aSyn in Lewy Bodies and Lewy neurites in disorders such as PD, dementia with Lewy bodies, or multiple system atrophy, suggests aSyn misfolding and aggregation plays an important role in these disorders, collectively known as synucleinopathies. The exact function of aSyn remains unclear, but it is known to be associated with vesicles and membranes, and to have an impact on important cellular functions such as intracellular trafficking and protein degradation systems, leading to cellular pathologies that can be readily studied in cell-based models. Thus, understanding the molecular effects of aSyn point mutations may provide important insight into the molecular mechanisms underlying disease onset. We investigated the effect of the recently identified A53E aSyn mutation. Combining in vitro studies with studies in cell models, we found that this mutation reduces aSyn aggregation and increases proteasome activity, altering normal proteostasis. We observed that, in our experimental paradigms, the A53E mutation affects specific steps of the aggregation process of aSyn and different cellular processes, providing novel ideas about the molecular mechanisms involved in synucleinopathies. - The online version of this article (doi:10. 1186/s40478-016-0402-8) contains supplementary material, which is available to authorized users.
Note:	Ajuts: TFO is supported by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain, by the German-Israeli Foundation for Scientific Research and Development (GIF), and by a grant from the Niedersachsisches Ministerium fur Wissenschaft und Kultur (MWK). TFO and SV are supported by a grant from Fundación La Marato de TV3 (Ref. 20144330). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Alpha-synuclein ; Parkinson's disease ; Oligomerization ; Aggregation ; Neurodegeneration
Published in:	Acta neuropathologica communications, Vol. 4 (2016) , art. 128, ISSN 2051-5960

DOI: 10.1186/s40478-016-0402-8
PMID: 27938414

15 p, 4.8 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Biotecnologia i de Biomedicina (IBB)
Articles > Research articles
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