Molecular Subtypes of Midbrain Dopaminergic Neurons and Their Roles in Parkinson’s Disease

Gaertner, Zachary Aaron

doi:https://doi.org/10.21985/n2-wh0q-vx54

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Molecular Subtypes of Midbrain Dopaminergic Neurons and Their Roles in Parkinson’s Disease

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Parkinson’s disease (PD) is the second most common neurodegenerative disorder, causing devastating disabilities in both motor and non-motor domains following the degeneration of dopamine (DA) producing neurons of the substantia nigra pars compacta (SNc). Current treatments are highly limited in efficacy, and no established treatments currently exist to alter disease course. To advance therapeutic outcomes, a better understanding of both what triggers the neurodegeneration in PD (i.e. cell-intrinsic mechanisms) as well as how this degeneration leads to motor deficits (i.e. circuit-level mechanisms) is necessary. The degeneration observed in PD is not uniform, with DA neurons in the ventral tier of the SNc (vSNc) being lost in far greater numbers compared to those in the dorsal tier SNc (dSNc). These findings of selective vulnerability have led to investigations into the molecular heterogeneity of midbrain DA neurons, with work from our lab and others establishing several putative molecular subtypes with specific anatomical distributions and projection patterns. Unfortunately, these studies have not arrived at a consensus in terms of DA subtypes, at least in part due to the technical limitations the experiments faced. In addition, while it is known that the vSNc degenerates to a greater degree than the dSNc, it is unclear what role this selective ventral tier degeneration plays in Parkinsonian motor deficits. Here, we have sought to address these gaps in the field. We first establish a high-resolution map of the DA neuron subtype landscape using single-nucleus RNA sequencing of DA neurons in mice. Next, we examine the functional responses of individual DA neuron subtypes, as well as create and characterize a novel PD mouse model through a subtype-specific ablation in order to demonstrate that loss of these specific subtypes can drive parkinsonian motor deficits. Finally, we utilize RNAseq datasets across conditions to explore potential genetic mechanisms underlying the vulnerability of specific vSNc subpopulations. Through this work, we demonstrate that DA molecular subtypes localized to the ventral tier have unique properties (such as their gene expression profiles, vulnerability and functional roles) that potentially drive the pathophysiology of PD. We hope that these advances will allow for targeted investigations into the pathophysiology and pathogenesis of human PD.

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