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

Nripesh Dhungel, Simona Eleuteri, Ling bo Li, Nicholas J. Kramer, Justin W. Chartron, Brian Spencer, Kori Kosberg, Jerel Adam Fields, Klodjan Stafa, Anthony Adame, Hilal Lashuel, Judith Frydman, Kang Shen, Eliezer Masliah, Aaron D. Gitler

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

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 α-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 α-synuclein pathobiology in yeast, worms, and mouse. Finally, we provide a resource of candidate PD genes for future interrogation.

Original languageEnglish
Pages (from-to)76-88
Number of pages13
JournalNeuron
Volume85
Issue number1
DOIs
Publication statusPublished - 7 Jan 2015
Externally publishedYes

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Synucleins
Parkinson Disease
Genes
Yeasts
Proteins
Neurodegenerative Diseases
Transgenic Mice
Up-Regulation
Animal Models
Neurons

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Dhungel, N., Eleuteri, S., Li, L. B., Kramer, N. J., Chartron, J. W., Spencer, B., ... Gitler, A. D. (2015). Parkinson's Disease Genes VPS35 and EIF4G1 Interact Genetically and Converge on α-Synuclein. Neuron, 85(1), 76-88. https://doi.org/10.1016/j.neuron.2014.11.027

Parkinson's Disease Genes VPS35 and EIF4G1 Interact Genetically and Converge on α-Synuclein. / Dhungel, Nripesh; Eleuteri, Simona; Li, Ling bo; Kramer, Nicholas J.; Chartron, Justin W.; Spencer, Brian; Kosberg, Kori; Fields, Jerel Adam; Stafa, Klodjan; Adame, Anthony; Lashuel, Hilal; Frydman, Judith; Shen, Kang; Masliah, Eliezer; Gitler, Aaron D.

In: Neuron, Vol. 85, No. 1, 07.01.2015, p. 76-88.

Research output: Contribution to journalArticle

Dhungel, N, Eleuteri, S, Li, LB, Kramer, NJ, Chartron, JW, Spencer, B, Kosberg, K, Fields, JA, Stafa, K, Adame, A, Lashuel, H, Frydman, J, Shen, K, Masliah, E & Gitler, AD 2015, 'Parkinson's Disease Genes VPS35 and EIF4G1 Interact Genetically and Converge on α-Synuclein', Neuron, vol. 85, no. 1, pp. 76-88. https://doi.org/10.1016/j.neuron.2014.11.027
Dhungel N, Eleuteri S, Li LB, Kramer NJ, Chartron JW, Spencer B et al. Parkinson's Disease Genes VPS35 and EIF4G1 Interact Genetically and Converge on α-Synuclein. Neuron. 2015 Jan 7;85(1):76-88. https://doi.org/10.1016/j.neuron.2014.11.027
Dhungel, Nripesh ; Eleuteri, Simona ; Li, Ling bo ; Kramer, Nicholas J. ; Chartron, Justin W. ; Spencer, Brian ; Kosberg, Kori ; Fields, Jerel Adam ; Stafa, Klodjan ; Adame, Anthony ; Lashuel, Hilal ; Frydman, Judith ; Shen, Kang ; Masliah, Eliezer ; Gitler, Aaron D. / Parkinson's Disease Genes VPS35 and EIF4G1 Interact Genetically and Converge on α-Synuclein. In: Neuron. 2015 ; Vol. 85, No. 1. pp. 76-88.
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