In Vivo Visual Screen for Dopaminergic Rab ↔ LRRK2-G2019S Interactions in Drosophila Discriminates Rab10 from Rab3

G3 (Bethesda). 2020 Jun 1;10(6):1903-1914. doi: 10.1534/g3.120.401289.

Abstract

LRRK2 mutations cause Parkinson's, but the molecular link from increased kinase activity to pathological neurodegeneration remains undetermined. Previous in vitro assays indicate that LRRK2 substrates include at least 8 Rab GTPases. We have now examined this hypothesis in vivo in a functional, electroretinogram screen, expressing each Rab with/without LRRK2-G2019S in selected Drosophila dopaminergic neurons. Our screen discriminated Rab10 from Rab3. The strongest Rab/LRRK2-G2019S interaction is with Rab10; the weakest with Rab3. Rab10 is expressed in a different set of dopaminergic neurons from Rab3. Thus, anatomical and physiological patterns of Rab10 are related. We conclude that Rab10 is a valid substrate of LRRK2 in dopaminergic neurons in vivo We propose that variations in Rab expression contribute to differences in the rate of neurodegeneration recorded in different dopaminergic nuclei in Parkinson's.

Keywords: Drosophila melanogaster; G2019S; LRRK2; Parkinson’s UK K-1704 G-1804; Parkinson’s disease; Rab10; Rab3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dopaminergic Neurons / metabolism
  • Drosophila* / genetics
  • Drosophila* / metabolism
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism
  • Mutation
  • Parkinson Disease* / genetics
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism

Substances

  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • rab GTP-Binding Proteins