Biology subjects

Stickley, L.

Publications and source records attributed to Stickley, L..

2 recordsLinked to original sources

bioRxiv2022

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

Parkinsons 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.

neuroscience↗

bioRxiv2020

Maintenance of mitochondrial integrity in midbrain dopaminergic neurons governed by a conserved developmental transcription factor

The degeneration of dopaminergic (DA) neurons in the substantia nigra is a hallmark of Parkinsons disease (PD). Dysregulation of developmental transcription factors is implicated in dopaminergic neurodegeneration, but the underlying molecular mechanisms remain largely unknown. Drosophila Fer2 is a prime example of a developmental transcription factor required for the birth and maintenance of midbrain DA neurons. Using an approach combining ChIP-seq, RNA-seq, and genetic epistasis experiments with PD-linked genes, here we demonstrate that Fer2 controls a transcriptional network to maintain mitochondrial structure and function, and thus confers dopaminergic neuroprotection against genetic and oxidative insults. We further show that conditional ablation of Nato3, a mouse homolog of Fer2, in differentiated DA neurons results in locomotor impairments and mitochondrial abnormality in aged mice. Our results reveal the essential and conserved role of Fer2 homologs in the mitochondrial maintenance of midbrain DA neurons, opening new perspectives for modelling and treating PD.

neuroscience↗