Parkinson's Disease Genes VPS35 and EIF4G1 Interact Genetically and Converge on α-Synuclein

被引：139

作者：

Dhungel, Nripesh ^{[1
]}

Eleuteri, Simona ^{[2
]}

Li, Ling-bo ^{[3
,4
]}

Kramer, Nicholas J. ^{[1
]}

Chartron, Justin W. ^{[1
,3
]}

Spencer, Brian ^{[2
]}

Kosberg, Kori ^{[2
]}

Fields, Jerel Adam ^{[5
]}

Stafa, Klodjan ^{[5
]}

Adame, Anthony ^{[2
]}

Lashuel, Hilal ^{[6
]}

Frydman, Judith ^{[1
,3
]}

Shen, Kang ^{[3
,4
]}

Masliah, Eliezer ^{[2
,5
]}

Gitler, Aaron D. ^{[1
]}

机构：

[1] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA

[2] Univ Calif San Diego, Sch Med, Dept Neurosci, La Jolla, CA 92093 USA

[3] Stanford Univ, Dept Biol, Stanford, CA 94305 USA

[4] Howard Hughes Med Inst, Stanford, CA 94305 USA

[5] Univ Calif San Diego, Sch Med, Dept Pathol, San Diego, CA 92093 USA

[6] Ecole Polytech Fed Lausanne, Sch Life Sci, Brain Mind Inst, Lab Mol & Chem Biol Neurodegenerat, CH-1015 Lausanne, Switzerland

来源：

NEURON | 2015年 / 85卷 / 01期

关键词：

UNFOLDED PROTEIN RESPONSE; GENOME-WIDE ASSOCIATION; NEURODEGENERATIVE DISORDERS; FRONTOTEMPORAL DEMENTIA; COMMON-CAUSE; YEAST; MUTATIONS; COMPLEX; PATHOLOGY; RETROMER;

D O I：

10.1016/j.neuron.2014.11.027

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Parkinson's disease (PD) is a common neurodegenerative disorder. Functional interactions between some PD genes, like PINK1 and parkin, have been identified, but whether other ones interact remains elusive. Here we report an unexpected genetic interaction between two PD genes, VPS35 and EIF4G1. We provide evidence that EIF4G1 upregulation causes defects associated with protein misfolding. Expression of a sortilin protein rescues these defects, downstream of VPS35, suggesting a potential role for sortilins in PD. We also show interactions between VPS35, EIF4G1, and alpha-synuclein, a protein with a key role in PD. We extend our findings from yeast to an animal model and show that these interactions are conserved in neurons and in transgenic mice. Our studies reveal unexpected genetic and functional interactions between two seemingly unrelated PD genes and functionally connect them to alpha-synuclein pathobiology in yeast, worms, and mouse. Finally, we provide a resource of candidate PD genes for future interrogation.

引用

页码：76 / 87

页数：12

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