Abberant protein synthesis in G2019S LRRK2 drosophila parkinson disease-related phenotypes

Ian Martin, Leire Abalde-Atristain, Jungwoo Wren Kim, Ted M. Dawson, Valina L. Dawson

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

LRRK2 mutations are a frequent cause of familial Parkinson disease (PD) and are also found in a number of sporadic PD cases. PD-linked G2019S and I2020T mutations in the kinase domain of LRRK2 result in elevated kinase activity, which is required for the toxicity of these pathogenic variants in cell and animal models of PD. We recently reported that LRRK2 interacts with and phosphorylates a number of mammalian ribosomal proteins, several of which exhibit increased phosphorylation via both G2019S and I2020T LRRK2. Blocking the phosphorylation of ribosomal protein s15 through expression of phospho-deficient T136A s15 prevents age-associated locomotor deficits and dopamine neuron loss caused by G2019S LRRK2 expression in Drosophila indicating that s15 is a pathogenic LRRK2 substrate. We previously described that G2019S LRRK2 causes an induction of bulk mRNA translation that is blocked by T136A s15 or the protein synthesis inhibitor anisomycin. Here, we report the protective effects of the eIF4E/eIF4G interaction inhibitor 4EGI-1, in preventing neurodegenerative phenotypes in G2019S LRRK2 flies, and discuss how our findings and those of other groups provide a framework to begin investigating the mechanistic impact of LRRK2 on translation.

Original languageEnglish (US)
Pages (from-to)165-169
Number of pages5
JournalFly
Volume8
Issue number3
DOIs
StatePublished - 2014
Externally publishedYes

Fingerprint

Parkinson disease
Drosophila
protein synthesis
phenotype
ribosomal proteins
translation (genetics)
phosphorylation
phosphotransferases (kinases)
mutation
protein synthesis inhibitors
dopamine
protective effect
neurons
animal models
toxicity
cells

Keywords

  • 4EGI-1
  • Anisomycin
  • LRRK2
  • Parkinson disease
  • S15

ASJC Scopus subject areas

  • Insect Science

Cite this

Abberant protein synthesis in G2019S LRRK2 drosophila parkinson disease-related phenotypes. / Martin, Ian; Abalde-Atristain, Leire; Kim, Jungwoo Wren; Dawson, Ted M.; Dawson, Valina L.

In: Fly, Vol. 8, No. 3, 2014, p. 165-169.

Research output: Contribution to journalArticle

Martin, Ian ; Abalde-Atristain, Leire ; Kim, Jungwoo Wren ; Dawson, Ted M. ; Dawson, Valina L. / Abberant protein synthesis in G2019S LRRK2 drosophila parkinson disease-related phenotypes. In: Fly. 2014 ; Vol. 8, No. 3. pp. 165-169.
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