Effect of different alpha-synuclein variants on astrocyte-neuron coupling


CALL: 2016

DOMAIN: BM - Life Sciences, Biology and Medicine


LAST NAME: Nicklas



HOST INSTITUTION: University of Luxembourg

KEYWORDS: Parkinson's disease, human iPSCs, astrocytes, dopaminergic neurons, alpha-synuclein, disease modelling, high-content imaging

START: 2017-08-01

END: 2017-11-30

WEBSITE: https://www.uni.lu

Submitted Abstract

With the advent of the iPSC technology it has become possible to generate patient-specific iPSCs making them a promising tool for studying disease-specific phenotypes in certain cell types. Such iPSCs have been generated for several neurological diseases, as for example Parkinson`s disease (PD). PD is an age-associated neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons of the substantia nigra. Mutations in several genes have been implicated in the development of PD, among which mutations in the LRRK2 gene represent the most common cause of familial PD. One of the major hallmarks of PD is the formation of so called Lewy Bodies, protein aggregates that primarily consist of a-synuclein. a-synuclein can also be secreted by neurons via exocytosis and can be taken up from neighboring neurons via endocytosis, contributing to the progression of disease pathology.Several studies have demonstrated, that dopaminergic neurons derived from human iPSCs were able to recapitulate some of the defects observed in PD patients, as for example increased susceptibility to oxidative stress or reduced neurite complexity. However, few studies have focused so far on the role of astrocytes in PD and the interplay of astrocytes and neurons in the context of disease progression. Astrocytes are the most common cell type in the mammalian brain and are critical for neuronal survival and function. Interestingly, a beneficial role of astrocytes has been shown in a rat model of amyotrophic lateral sclerosis, in which transplantation of wild-type astrocyte precursors lead to a substantial extension of motor neuron survival.Therefore, we aim to analyze the effect of a-synuclein on human astrocytes and on their interplay with dopaminergic neurons. To this end, we will make use of isogenic pairs of iPSC-derived human astrocytes and dopaminergic neurons from healthy individuals as well as from PD patients carrying the LRRK2-G2019S mutation. These cells will be treated with wildtype a-synuclein, post-translationally modified a-synuclein, or fibers of a-synuclein. We will then analyze whether these different a-synuclein variants can be taken up by astrocytes and neurons and their effects on cellular phenotypes. Furthermore, we aim to investigate the spreading behavior of the different variants between both cell types and possible differences in astrocyte-to-neuron coupling. In this context, it will also be interesting to analyze, whether the co-culture of mature healthy astrocytes with healthy or diseased dopaminergic neurons has any beneficial effect on these neurons after a-synuclein treatment. Finally, we aim to scale up this system by using high-content imaging, to be able to screen for phenotypic differences in various cell lines or for drugs that may revert these phenotypes.

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