RT Journal Article
SR Electronic
T1 A Druggable Genome Screen Identifies Modifiers of α-Synuclein Levels via a Tiered Cross-Species Validation Approach
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 9286
OP 9301
DO 10.1523/JNEUROSCI.0254-18.2018
VO 38
IS 43
A1 Maxime W.C. Rousseaux
A1 Gabriel E. Vázquez-Vélez
A1 Ismael Al-Ramahi
A1 Hyun-Hwan Jeong
A1 Aleksandar Bajić
A1 Jean-Pierre Revelli
A1 Hui Ye
A1 Emily T. Phan
A1 Jennifer M. Deger
A1 Alma M. Perez
A1 Ji-Yoen Kim
A1 Laura A. Lavery
A1 Qikia Xu
A1 Mamie Z. Li
A1 Hyojin Kang
A1 Jean J. Kim
A1 Joshua M. Shulman
A1 Thomas F. Westbrook
A1 Stephen J. Elledge
A1 Zhandong Liu
A1 Juan Botas
A1 Huda Y. Zoghbi
YR 2018
UL http://www.jneurosci.org/content/38/43/9286.abstract
AB Accumulation of α-Synuclein (α-Syn) causes Parkinson's disease (PD) as well as other synucleopathies. α-Syn is the major component of Lewy bodies and Lewy neurites, the proteinaceous aggregates that are a hallmark of sporadic PD. In familial forms of PD, mutations or copy number variations in SNCA (the α-Syn gene) result in a net increase of its protein levels. Furthermore, common risk variants tied to PD are associated with small increases of wild-type α-Syn levels. These findings are further bolstered by animal studies which show that overexpression of α-Syn is sufficient to cause PD-like features. Thus, increased α-Syn levels are intrinsically tied to PD pathogenesis and underscore the importance of identifying the factors that regulate its levels. In this study, we establish a pooled RNAi screening approach and validation pipeline to probe the druggable genome for modifiers of α-Syn levels and identify 60 promising targets. Using a cross-species, tiered validation approach, we validate six strong candidates that modulate α-Syn levels and toxicity in cell lines, Drosophila, human neurons, and mouse brain of both sexes. More broadly, this genetic strategy and validation pipeline can be applied for the identification of therapeutic targets for disorders driven by dosage-sensitive proteins.SIGNIFICANCE STATEMENT We present a research strategy for the systematic identification and validation of genes modulating the levels of α-Synuclein, a protein involved in Parkinson's disease. A cell-based screen of the druggable genome (>7,500 genes that are potential therapeutic targets) yielded many modulators of α-Synuclein that were subsequently confirmed and validated in Drosophila, human neurons, and mouse brain. This approach has broad applicability to the multitude of neurological diseases that are caused by mutations in genes whose dosage is critical for brain function.