Our previous genome-wide screens against alpha-synuclein toxicity in the genetically tractable Baker’s yeast cell guided us to discover cellular pathologies in patient stem cell-derived neurons from synucleinopathy patients (Chung*, Khurana* Science 2013). We are developing the requisite tools to now to establish these kinds of genetic screening technologies directly in patient stem cell-derived neurons.
In two subsequent papers (Cell Systems 2017), along with our collaborators, we have developed (Picture 1):
- GENOME-SCALE MAPS: that systematically analyze the genes and cellular processes involved in alpha-synuclein toxicity through multiple genome-wide genetic screens
- PROTEOME-SCALE MAPS that map the neighboring proteome of alpha-synuclein within neurons using a variety of in situ proteome approaches
- COMPUTATIONAL TOOLS to integrate these genetic and spatial maps, identifying important overlaps.
Insights from these methods allowed us to uncover previously unknown facets of alpha-synuclein biology and pathology in patient stem cell-derived neurons, including major direct effects on vesicle trafficking and mRNA metabolism.