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

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, afflicting over 1% of the population of age 60 years and above. The loss of dopaminergic (DA) neurons is 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 divers that enable genetic manipulation of a small number of defined cell population. We identify a subtype of DA neurons selectively vulnerable in the model of the 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 aging-related research: the age-dependent increase in the number of GAL4-labeled cells.