The Drosophila hep pathway mediates Lrrk2-induced neurodegeneration

Dejun Yang, Joseph M. Thomas, Tianxia Li, Youngseok Lee, Zhaohui Liu, Wanli Smith

Research output: Contribution to journalArticle

Abstract

Although the pathogenesis of Parkinson's disease (PD) remains unclear, mutations in leucine-rich repeat kinase 2 (Lrrk2) are among the major causes of familial PD. Most of these mutations disrupt Lrrk2 kinase and (or) GTPase domain function, resulting in neuronal degeneration. However, the signal pathways underlying Lrrk2-induced neuronal degeneration are not fully understood. There is an expanding body of evidence that suggests a link between Lrrk2 function and MAP kinase (MAPK) cascades. To further investigate this link in vivo, genetic RNAi screens of the MAPK pathways were performed in a Drosophila model to identify genetic modifier(s) that can suppress G2019S-Lrrk2-induced PD-like phenotypes. The results revealed that the knockdown of hemipterous (hep, or JNKK) increased fly survival time, improved locomotor function, and reduced loss of dopaminergic neurons in G2019S-Lrrk2 transgenic flies. Expression of the dominant-negative allele of JNK (JNK-DN), a kinase that is downstream of hep in G2019S-Lrrk2 transgenic flies, elicited a similar effect. Moreover, treatment with the JNK inhibitor SP600125 partially reversed the G2019S-Lrrk2-induced loss of dopaminergic neurons. These results indicate that the hep pathway plays an important role in Lrrk2-linked Parkinsonism in flies. These studies provide new insights into the molecular mechanisms underlying Lrrk2-linked PD pathogenesis and aid in identifying potential therapeutic targets.

Original languageEnglish (US)
Pages (from-to)441-449
Number of pages9
JournalBiochemistry and Cell Biology
Volume96
Issue number4
DOIs
StatePublished - Jan 1 2018

Fingerprint

Leucine
Drosophila
Phosphotransferases
Diptera
Parkinson Disease
Dopaminergic Neurons
Neurons
Mutation
MAP Kinase Signaling System
GTP Phosphohydrolases
Parkinsonian Disorders
RNA Interference
Signal Transduction
Alleles
Phenotype

Keywords

  • Dopamine neuron
  • Drosophila model
  • hep
  • JNK
  • Lrrk2
  • Neuronal degeneration
  • Parkinson's disease

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

The Drosophila hep pathway mediates Lrrk2-induced neurodegeneration. / Yang, Dejun; Thomas, Joseph M.; Li, Tianxia; Lee, Youngseok; Liu, Zhaohui; Smith, Wanli.

In: Biochemistry and Cell Biology, Vol. 96, No. 4, 01.01.2018, p. 441-449.

Research output: Contribution to journalArticle

Yang, Dejun ; Thomas, Joseph M. ; Li, Tianxia ; Lee, Youngseok ; Liu, Zhaohui ; Smith, Wanli. / The Drosophila hep pathway mediates Lrrk2-induced neurodegeneration. In: Biochemistry and Cell Biology. 2018 ; Vol. 96, No. 4. pp. 441-449.
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