There is great interest in the compensatory mechanisms that may function to delay onset of symptoms in the early/presymptomatic phase of Parkinson?s Disease. Here we use Drosophila and mouse models of dopamine (DA) deficiency to characterize compensatory mechanisms that may be relevant to the human condition. In the previous grant period, we partly localized a genetic element responsible for the ?Dopamine Bypass? phenotype, hereafter referred to as ?DD-Hi?, where ?DD? refers to Dopamine Deficient. DD-Hi flies show near normal levels of locomotor activity despite total deficiency of brain dopamine (DA), compared to the low locomotor activity DA deficient line, DD-Lo. The work proposed for the upcoming grant period will work toward more precise genetic mapping of this trait. Related aims will contribute to this effort, identifying and characterizing a co-transmitter that functions in DA neurons that are devoid of dopamine, and analyzing the transcriptomes of single DA neurons. We will pursue a parallel model in mice, where mice that are made dopamine deficient in specific brain regions provide evidence for a dopamine dependent autoregulatory loop that leads to continued expression of a set of genes required for development and maintenance of DA neurons, particularly in the SNc (substantia nigra pars compacta). Given the high susceptibility of SNc DA neurons in early Parkinsons Disease, confirmation of this regulatory circuit could have both clinical and basic science implications. Our hope is that pursuing analogous models in flies and mice will aid in identification of conserved genes and mechanisms that will inform therapeutic targets and strategies in humans.
Dopamine is an important and evolutionarily conserved neurotransmitter with significant neuromodulatory roles that are conserved between insects and humans. Here we study parallel models of dopamine loss in fruit fly and mouse models, utilizing the two animal models to aid in identification of conserved mechanisms that assist in compensating for this loss. These studies have the potential to contribute to our understanding of mechanisms that delay onset of symptoms in the early/presymptomatic phase of human Parkinsons Disease.
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