Embryonic stem cell‐derived neuron models of Parkinson's disease exhibit delayed neuronal death

H Yamashita, T Nakamura, T Takahashi… - Journal of …, 2006 - Wiley Online Library
H Yamashita, T Nakamura, T Takahashi, Y Nagano, M Hiji, T Hirabayashi, T Amano, T Yagi…
Journal of neurochemistry, 2006Wiley Online Library
Establishment of a Parkinson's disease (PD) neuron model was attempted with mouse
embryonic stem (ES) cells. ES cell lines over‐expressing mouse nuclear receptor‐related 1
(Nurr1), together with human wild‐type and alanine 30→ proline (A30P) and alanine 53→
threonine (A53T) mutant α‐synuclein were established and subjected to differentiation into
dopaminergic neurons. The ES cell‐derived dopaminergic neurons expressing wild‐type or
mutant α‐synuclein exhibited the fundamental characteristics consistent with dopaminergic …
Abstract
Establishment of a Parkinson's disease (PD) neuron model was attempted with mouse embryonic stem (ES) cells. ES cell lines over‐expressing mouse nuclear receptor‐related 1 (Nurr1), together with human wild‐type and alanine 30 → proline (A30P) and alanine 53 → threonine (A53T) mutant α‐synuclein were established and subjected to differentiation into dopaminergic neurons. The ES cell‐derived dopaminergic neurons expressing wild‐type or mutant α‐synuclein exhibited the fundamental characteristics consistent with dopaminergic neurons in the substantia nigra. The ES cell‐derived PD model neurons exhibited increased susceptibility to oxidative stress, proteasome inhibition, and mitochondrial inhibition. Cell viability of PD model neurons and the control neurons was similar until 28 days after differentiation. Nonetheless, after that time, PD model neurons gradually began to undergo neuronal death over the course of 1 month, showing cytoplasmic aggregate formation and an increase of insoluble α‐synuclein protein. Such delayed neuronal death was observed in a mutant α‐synuclein protein level‐dependent manner, which was slightly inhibited by a c‐jun N‐terminal kinase inhibitor and a caspase inhibitor. Such cell death was not observed when the same ES cell lines were differentiated into oligodendrocytes. The ES cell‐derived PD model neurons are considered as prospective candidates for a new prototype modelling PD that would allow better investigation of the underlying neurodegenerative pathophysiology.
Wiley Online Library