The Drosophila hep pathway mediates Lrrk2-induced neurodegeneration

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

Research output: Contribution to journalArticlepeer-review

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 - 2018

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'The Drosophila hep pathway mediates Lrrk2-induced neurodegeneration'. Together they form a unique fingerprint.

Cite this