The utility and caveat of split-GAL4s in the study of neurodegeneration

Fly (Austin). 2023 Dec;17(1):2192847. doi: 10.1080/19336934.2023.2192847.


Parkinson's disease (PD) is the second most common neurodegenerative disorder, afflicting over 1% of the population of age 60 y and above. The loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) is the primary cause of its characteristic motor symptoms. Studies using Drosophila melanogaster and other model systems have provided much insight into the pathogenesis of PD. However, little is known why certain cell types are selectively susceptible to degeneration in PD. Here, we describe an approach to identify vulnerable subpopulations of neurons in the genetic background linked to PD in Drosophila, using the split-GAL4 drivers that enable genetic manipulation of a small number of defined cell populations. We identify split-GAL4 lines that target neurons selectively vulnerable in a model of leucine-rich repeat kinase 2 (LRRK2)-linked familial PD, demonstrating the utility of this approach. We also show an unexpected caveat of the split-GAL4 system in ageing-related research: an age-dependent increase in the number of GAL4-labelled cells.

Keywords: LRRK2; PAM neurons; Parkinson’s disease; Split-GAL4; dopaminergic neurons; neurodegeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / pathology
  • Drosophila / genetics
  • Drosophila / metabolism
  • Drosophila Proteins* / genetics
  • Drosophila Proteins* / metabolism
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism
  • Mice, Transgenic
  • Parkinson Disease* / genetics
  • Transcription Factors / metabolism


  • Drosophila Proteins
  • GAL4 protein, Drosophila
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Transcription Factors

Grants and funding

This work was supported by the funding by the Swiss National Science Foundation (310030_189169).