Transcriptome responses to reduced dopamine in the Substantia Nigra Pars Compacta reveals a potential protective role for dopamine

Abstract

Parkinson's Disease (PD), is a neurodegenerative disorder affecting both cognitive and motor functions. It is characterized by decreased brain dopamine (DA) and a selective and progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), whereas dopaminergic neurons in the ventral tegmental area (VTA) show reduced vulnerability. The majority of animal models of PD are genetic lesion or neurotoxin exposure models that lead to death of dopaminergic neurons. Here we use a DAT:TH KO mouse model that by inactivation of the tyrosine hydroxylase (Th) gene in dopamine transporter-expressing neurons, causes selective depletion of striatal dopamine without affecting DA neuron survival. We analyzed transcriptome responses to decreased DA in both pre-and post-synaptic dopaminergic brain regions of DAT:TH KO animals. We detected only few differentially expressed genes in the post-synaptic regions as a function of DA deficiency. This suggests that the broad striatal transcriptional changes in neurodegeneration-based PD models are not direct effects of DA depletion, but are rather a result of DA neuronal death. However, we find a number of dopaminergic genes differentially expressed in SNc, and to a lesser extent in VTA, as a function of DA deficiency, providing evidence for a DA-dependent feedback loop. Of particular interest, expression of Nr4a2, a crucial transcription factor maintaining DA neuron identity, is significantly decreased in SNc, but not VTA, of DAT:TH KO mice, implying a potential protective role for DA in the SNc.

Brain-wide transcriptome-based metabolic alterations in Parkinson’s disease: human inter-region and human-experimental model correlations

“…5b ), which are tissues within the BG and are known to influence different PD phenotypes 13 , was intriguing and might suggest that neuronal degeneration during PD extends to the putamen but less to striatum. This finding augurs well with a recent finding from a mouse model suggesting the independence of these regions 47 . A strong local interconnectivity between SN and cerebral cortical tissues has recently been shown 2,48 and the findings here suggest that such interconnectivity is also present at the differential expression of metabolic genes level.…”