Unity Walk > The Parkinson's Institute and Clinical Center Research Grants 2013

 

The Parkinson's Institute and Clinical Center is using its 2013 distribution to fund:

What Does Alpha-synuclein Accumulation in Glia Have to do with Parkinsonism?

PROJECT TITLE:  What Does Alpha-synuclein Accumulation in Glia Have to do with Parkinsonism?

Investigators/Authors: Birgitt Schuele, MD, Director for Gene Discovery and Stem Cell Modeling; J. William Langston, MD, CEO and Founder

Objective: The goal of this study is to derive induced pluripotent stem cell (iPSC) lines from patients with multiple system atrophy (MSA) and assess expression and accumulation of alpha-synuclein in patient-specific differentiated oligodendrocytes.

Background: MSA is a form of atypical parkinsonism that presents as a more severe and rapidly progressing form of Parkinson’s Disease (PD) with autonomic failure.  A distinctive feature of the disease (in addition to the degeneration of certain neuronal populations) is the presence of glial cytoplasmic inclusion bodies (GCIs). In MSA, these inclusions are observed in a type of glia known as oligodendrocytes and importantly contain alpha-synuclein aggregates. At the moment, their role in MSA is a complete mystery. Although several iPSC-based model systems have been reported for genetically linked forms of PD, MSA iPSC models have not been established to date.  

Methods/Design: In Aim 1, we will derive three MSA iPSC lines from patients with the disease and matched controls. We will use established protocols from our laboratory with Sendaivirus for footprint-free reprogamming. All derived clones will be characterized based on standards set forward by the International Society for Stem Cell Research. In Aim 2, we will differentiate the iPSC lines into precursor cells and then further differentiate them into oligodendrocytes using a newly established protocol by Tesar et al. 2011 which will be adapted to human. In the last Aim, we will assess alpha-synuclein in oligodendrocytes by measuring expression of total alpha-synuclein, alpha-synuclein aggregation, and post-translational modifications using immunoblotting and immunocytochemistry techniques. We will further test, if knockdown by gene engineering (TALEN) of alpha-synuclein in these iPSCs will reverse any observed phenotype(s).

Relevance to Diagnosis/Treatment of Parkinson’s disease: The lack of established animal models that accurately recapitulate MSA or PD, and access to the cell types that are most affected in these disorders - human neurons/glia- is extremely limiting. The promise of stem cell technologies, such as the ability to create relevant cell types, to manipulate, engineer, and study these cells and tissues, opens new avenues for disease research and drug discovery.  Importantly, protein misfolding and aggregation of alpha-synuclein is a common feature across synucleinopathies and an attractive target for drug development. Thus this novel project could provide vital insights into the role of alpha-synuclein for all forms of parkinsonism that involve alpha-synuclein aggregation, including typical Parkinson’s disease.

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