Protein-protein interactions reveal key canonical pathways, upstream regulators, interactome domains, and novel targets in ALS

被引:29
作者
Dervishi, Ina [1 ]
Gozutok, Oge [1 ]
Murnan, Kevin [1 ]
Gautam, Mukesh [1 ]
Heller, Daniel [1 ]
Bigio, Eileen [2 ,3 ]
Ozdinler, P. Hande [1 ,2 ,4 ,5 ]
机构
[1] Northwestern Univ, Feinberg Sch Med, Dept Neurol, Chicago, IL 60611 USA
[2] Mesulam Cognit Neurol & Alzheimer Dis Ctr, Chicago, IL 60611 USA
[3] Northwestern Univ, Dept Pathol, Chicago, IL 60611 USA
[4] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Feinberg Sch Med, Chicago, IL 60611 USA
[5] Northwestern Univ, Feinberg Sch Med, Les Turner ALS Ctr, Chicago, IL 60611 USA
来源
SCIENTIFIC REPORTS | 2018年 / 8卷
关键词
AMYOTROPHIC-LATERAL-SCLEROSIS; CILIARY NEUROTROPHIC FACTOR; GAMMA PPAR-GAMMA; GROWTH-FACTOR; ENDOPLASMIC-RETICULUM; LIPID-METABOLISM; GENE-EXPRESSION; SURVIVAL; NEURONS; BINDING;
D O I
10.1038/s41598-018-32902-4
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Developing effective treatment strategies for neurodegenerative diseases require an understanding of the underlying cellular pathways that lead to neuronal vulnerability and progressive degeneration. To date, numerous mutations in 147 distinct genes are identified to be "associated" with, "modifier" or "causative" of amyotrophic lateral sclerosis (ALS). Protein products of these genes and their interactions helped determine the protein landscape of ALS, and revealed upstream modulators, key canonical pathways, interactome domains and novel therapeutic targets. Our analysis originates from known human mutations and circles back to human, revealing increased PPARG and PPARGC1A expression in the Betz cells of sALS patients and patients with TDP43 pathology, and emphasizes the importance of lipid homeostasis. Downregulation of YWHAZ, a 14-3-3 protein, and cytoplasmic accumulation of ZFYVE27 especially in diseased Betz cells of ALS patients reinforce the idea that perturbed protein communications, interactome defects, and altered converging pathways will reveal novel therapeutic targets in ALS.
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页数:19
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