Wednesday, October 24, 2018

Drosophila studies help identify mutations in NUS1 as contributors to Parkinson's Disease

Guo JF, Zhang L, Li K, Mei JP, Xue J, Chen J, Tang X, Shen L, Jiang H, Chen C, Guo H, Wu XL, Sun SL, Xu Q, Sun QY, Chan P, Shang HF, Wang T, Zhao GH, Liu JY, Xie XF, Jiang YQ, Liu ZH, Zhao YW, Zhu ZB, Li JD, Hu ZM, Yan XX, Fang XD, Wang GH, Zhang FY, Xia K, Liu CY, Zhu XW, Yue ZY, Li SC, Cai HB, Zhang ZH, Duan RH, Tang BS. Coding mutations in NUS1 contribute to Parkinson's disease. Proc Natl Acad Sci U S A. 2018 Oct 22. pii: 201809969. PMID: 30348779.

The abstract: "Whole-exome sequencing has been successful in identifying genetic factors contributing to familial or sporadic Parkinson's disease (PD). However, this approach has not been applied to explore the impact of de novo mutations on PD pathogenesis. Here, we sequenced the exomes of 39 early onset patients, their parents, and 20 unaffected siblings to investigate the effects of de novo mutations on PD. We identified 12 genes with de novo mutations (MAD1L1, NUP98, PPP2CB, PKMYT1, TRIM24, CEP131, CTTNBP2, NUS1, SMPD3, MGRN1, IFI35, and RUSC2), which could be functionally relevant to PD pathogenesis. Further analyses of two independent case-control cohorts (1,852 patients and 1,565 controls in one cohort and 3,237 patients and 2,858 controls in the other) revealed that NUS1 harbors significantly more rare nonsynonymous variants (P = 1.01E-5, odds ratio = 11.3) in PD patients than in controls. Functional studies in Drosophila demonstrated that the loss of NUS1 could reduce the climbing ability, dopamine level, and number of dopaminergic neurons in 30-day-old flies and could induce apoptosis in fly brain. Together, our data suggest that de novo mutations could contribute to early onset PD pathogenesis and identify NUS1 as a candidate gene for PD."

Thursday, October 11, 2018

Drosophila research studies contribute to patient diagnosis for patients with previously undiagnosed diseases

Splinter et al. Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease. New England Journal of Medicine. DOI: 10.1056/NEJMoa1714458

This article, which can be accessed free at NEJM, includes a description of how studies in Drosophila and other model systems contribute to identification by the Undiagnosed Diseases Network of disease-causing variants in genome data from previously undiagnosed patients. As stated in the article, "The model organisms screening center was directly involved in the diagnosis of eight patients in this study."

Monday, October 1, 2018

Cross-species study to identify modifiers of alpha-synuclein levels

Rousseaux MWC, Vázquez-Vélez GE, Al-Ramahi I, Jeong HH, Bajic A, Revelli JP, Ye H, Phan ET, Deger JM, Perez AM, Kim JY, Lavery LA, Xu Q, Li MZ, Kang H, Kim JJ, Shulman JM, Westbrook TF, Elledge SJ, Liu Z, Botas J, Zoghbi HY. A druggable genome screen identifies modifiers of α-synuclein levels via a tiered cross-species validation approach. J Neurosci. 2018 Sep 24. pii: 0254-18. PMID: 30249792.

From the abstract: "Accumulation of α-Synuclein (α-Syn) causes Parkinson's disease (PD) as well as other synucleopathies. ... 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. ... 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."