title: Protective role of olesoxime against wild-type α-synuclein-induced toxicity in human neuronally differentiated SHSY-5Y cells.
abstract: OBJECTIVE
  Parkinson's disease (PD) is usually diagnosed clinically from classical motor symptoms, while definitive diagnosis is made postmortem, based on the presence of Lewy bodies and nigral neuron cell loss. α-Synuclein (ASYN), the main protein component of Lewy bodies, clearly plays a role in the neurodegeneration that characterizes PD. Additionally, mutation in the SNCA gene or copy number variations are associated with some forms of familial PD. Here, the objective of the study was to evaluate whether olesoxime, a promising neuroprotective drug can prevent ASYN-mediated neurotoxicity.
  
  
  METHODS
  We used here a novel, mechanistically approachable and attractive cellular model based on the inducible overexpression of human wild-type ASYN in neuronally differentiated human neuroblastoma (SHSY-5Y) cells. This model demonstrates gradual cellular degeneration, coinciding temporally with the appearance of soluble and membrane-bound ASYN oligomers and cell death combining both apoptotic and non-apoptotic pathways.
  
  
  RESULTS
  Olesoxime fully protected differentiated SHSY-5Y cells from cell death, neurite retraction and cytoplasmic shrinkage induced by moderate ASYN overexpression. This protection was associated with a reduction in cytochrome c release from mitochondria and caspase-9 activation suggesting that olesoxime prevented ASYN toxicity by preserving mitochondrial integrity and function. In addition, olesoxime displayed neurotrophic effects on neuronally differentiated SHSY-5Y cells, independent of ASYN expression, by promoting their differentiation.
  
  
  CONCLUSIONS
  Because ASYN is a common underlying factor in many cases of PD, olesoxime could be a promising therapy to slow neurodegeneration in PD.
authors.affiliation: Trophos, Parc Scientifique de Luminy, Luminy Biotech Entreprises, Marseille, France.
authors.forename: C
authors.initials: C
authors.lastname: Gouarné
authors.forename: J
authors.initials: J
authors.lastname: Tracz
authors.forename: M Giraudon
authors.initials: MG
authors.lastname: Paoli
authors.forename: V
authors.initials: V
authors.lastname: Deluca
authors.forename: M
authors.initials: M
authors.lastname: Seimandi
authors.forename: G
authors.initials: G
authors.lastname: Tardif
authors.forename: M
authors.initials: M
authors.lastname: Xilouri
authors.forename: L
authors.initials: L
authors.lastname: Stefanis
authors.forename: T
authors.initials: T
authors.lastname: Bordet
authors.forename: R M
authors.initials: RM
authors.lastname: Pruss
mesh_terms: D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002783:Cholestenones / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D002783:Cholestenones; D018696:Neuroprotective Agents; D051844:alpha-Synuclein; D045304:Cytochromes c; C522838:olesoxime; D020169:Caspases