Περίληψη:
Background and PurposeParkinson’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. -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.
Experimental ApproachWe 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.
Key ResultsOlesoxime 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 and ImplicationsBecause ASYN is a common underlying factor
in many cases of PD, olesoxime could be a promising therapy to slow
neurodegeneration in PD.
Συγγραφείς:
Gouarne, C.
Tracz, J.
Paoli, M. Giraudon
Deluca, V. and
Seimandi, M.
Tardif, G.
Xilouri, M.
Stefanis, L.
Bordet,
T.
Pruss, R. M.
