Abstract
ObjectiveNeuronal loss in the substantia nigra pars compacta (SNpc) in Parkinson disease (PD) is not uniform, as dopamine neurons from the ventral tier are lost more rapidly than those of the dorsal tier. Identifying the intrinsic differences that account for this differential vulnerability may provide a key for developing new treatments for PD.MethodsHere, we compared the RNA‐sequenced transcriptomes of ~100 laser captured microdissected SNpc neurons from each tier from 7 healthy controls.ResultsExpression levels of dopaminergic markers were similar across the tiers, whereas markers specific to the neighboring ventral tegmental area were virtually undetected. After accounting for unwanted sources of variation, we identified 106 differentially expressed genes (DEGs) between the SNpc tiers. The genes higher in the dorsal/resistant SNpc tier neurons displayed coordinated patterns of expression across the human brain, their protein products had more interactions than expected by chance, and they demonstrated evidence of functional convergence. No significant shared functionality was found for genes higher in the ventral/vulnerable SNpc tier. Surprisingly but importantly, none of the identified DEGs was among the familial PD genes or genome‐wide associated loci. Finally, we found some DEGs in opposite tier orientation between human and analogous mouse populations.InterpretationOur results highlight functional enrichments of vesicular trafficking, ion transport/homeostasis and oxidative stress genes showing higher expression in the resistant neurons of the SNpc dorsal tier. Furthermore, the comparison of gene expression variation in human and mouse SNpc populations strongly argues for the need of human‐focused omics studies. ANN NEUROL 2020;87:853–868
Highlights
Transcriptional Signature of DA Neurons We confirmed the DA identity of our samples (Fig 2A) by looking at the transcript levels of dopamine transporters (VMAT and DAT), enzymes involved in the synthesis of dopamine (TH and DDC), and transcription factors involved in dopamine specification and maintenance
Our study focused on comparing the RNA-seq transcriptomic profiles of the ventral and dorsal tiers of substantia nigra pars compacta (SNpc) neurons in healthy individuals as we sought to identify intrinsic differences between the 2 neuronal populations that could inform on their differential vulnerability in the context of Parkinson disease (PD)
Performing the comparison among healthy individuals aids in capturing similar numbers of neurons from both tiers; the selection of cells is not biased toward only surviving neurons, as might occur if the same neuronal populations were compared between PD patients and healthy controls
Summary
Neuronal loss in the substantia nigra pars compacta (SNpc) in Parkinson disease (PD) is not uniform, as dopamine neurons from the ventral tier are lost more rapidly than those of the dorsal tier. DNA microarrays have been the most frequently used technique by which numerous gene expression studies have compared the postmortem brain tissue of PD patients to healthy controls, with varying results (see Zheng et al[6] for meta-analysis) The majority of these studies have, used SNpc bulk tissue, where the subpopulations are not identified and the cellular composition is affected by the neurodegenerative process itself, including reactive astrogliosis and microglial activation. For the first time in humans, we compared the RNA-seq–derived transcriptomes of laser capture microdissected (LCM) ventral (vulnerable) and dorsal (resistant) tier neurons of the SNpc from healthy individuals, to gain insight into the intrinsic differences between these neuronal populations that could explain their differential vulnerability in disease.
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