title: Alpha synuclein dimers and oligomers are increased in overexpressing conditions in vitro and in vivo.
abstract: Parkinson's disease is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta along with the formation of intracellular fibrillar inclusions (Lewy bodies and Lewy neuritis), which are mainly composed of aggregated α-synuclein (ASYN). This latter is a 14 kDa protein that localizes to synaptic vesicles in nerve terminals and promotes soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex assembly. We explored the monomeric and oligomeric state of ASYN in vitro in HEK293s and SH-SY5Y cell lines. In addition rats were injected in the substantia nigra with an Adeno associated virus carrying the human A53T mutation of ASYN (in vivo experiments). We show that human wild type ASYN as well as PD-linked mutations (A30P, E46K and A53T) in overexpressing conditions mostly exists in a monomeric state in equilibrium with dimeric forms. The monomer/dimer ratio is unaffected by PD-linked mutation. Furthermore, the A30P, E46K and A53T mutations overexpression strongly increased cell death compared to wild type ASYN. Taken together, our data suggest that ASYN dimers amount do not directly correlate to reduced cellular viability, suggesting a different role in protein function and induced pathology. Our data suggest that early ASYN neuro-pathogenic effects are probably mediated by other molecular processes than increased oligomerization alone.
authors.affiliation: UCB Biopharma S.P.R.L., Neuroscience TA, Chemin du Foriest B-1420 Braine l'Alleud, Belgium. Electronic address: daniele.marmolino@ucb.com.
authors.forename: D
authors.initials: D
authors.lastname: Marmolino
authors.affiliation: UCB Biopharma S.P.R.L., Molecular Biology & Gene Expression, Discovery Research, Chemin du Foriest B-1420 Braine l'Alleud, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Foerch
authors.affiliation: UCB Biopharma S.P.R.L., Non-Clinical Development, Chemin du Foriest B-1420 Braine l'Alleud, Belgium.
authors.forename: F A
authors.initials: FA
authors.lastname: Atienzar
authors.affiliation: UCB Biopharma S.P.R.L., Neuroscience TA, Chemin du Foriest B-1420 Braine l'Alleud, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Staelens
authors.affiliation: UCB Biopharma S.P.R.L., Neuroscience TA, Chemin du Foriest B-1420 Braine l'Alleud, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Michel
authors.affiliation: UCB Biopharma S.P.R.L., Neuroscience TA, Chemin du Foriest B-1420 Braine l'Alleud, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Scheller
mesh_terms: D000818:Animals; D016923:Cell Death; D045744:Cell Line, Tumor; D059290:Dopaminergic Neurons / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation; D055503:Protein Multimerization; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein
keywords: Alpha synuclein; Parkinson's disease; Toxicity