Spatial RNA Sequencing Identifies Robust Markers of Vulnerable and Resistant Human Midbrain Dopamine Neurons and Their Expression in Parkinson's Disease

Defining transcriptional profiles of substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) dopamine neurons is critical to understanding their differential vulnerability in Parkinson's Disease (PD). Here, we determine transcriptomes of human SNc and VTA dopamine neurons using LCM-seq on a large sample cohort. We apply a bootstrapping strategy as sample input to DESeq2 and identify 33 stably differentially expressed genes (DEGs) between these two subpopulations. We also compute a minimal sample size for identification of stable DEGs, which highlights why previous reported profiles from small sample sizes display extensive variability. Network analysis reveal gene interactions unique to each subpopulation and highlight differences in regulation of mitochondrial stability, apoptosis, neuronal survival, cytoskeleton regulation, extracellular matrix modulation as well as synapse integrity, which could explain the relative resilience of VTA dopamine neurons. Analysis of PD tissues showed that while identified stable DEGs can distinguish the subpopulations also in disease, the SNc markers SLIT1 and ATP2A3 were down-regulated and thus appears to be biomarkers of disease. In summary, our study identifies human SNc and VTA marker profiles, which will be instrumental for studies aiming to modulate dopamine neuron resilience and to validate cell identity of stem cell-derived dopamine neurons.

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Neurovetenskaper hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Neurosciences hsv//eng
human midbrain dopamine neurons
spatial transcriptomics
laser microdissection
RNA sequencing
substantia nigra compacta
ventral tegmental area
Parkinson's disease

Cheng, Shangli (author)
Kee, NigelStockholms universitet,Institutionen för biokemi och biofysik,Karolinska Institutet, Sweden(Swepub:su)nike0958 (author)
Cao, Ming (author)
Wang, Menghan (author)
Deng, QiaolinKarolinska Institutet (author)
Hedlund, EvaStockholms universitet,Institutionen för biokemi och biofysik,Karolinska Institutet, Sweden(Swepub:su)evhe5970 (author)
Stockholms universitetInstitutionen för biokemi och biofysik (creator_code:org_t)

By the author/editor: Aguila, Julio; Cheng, Shangli; Kee, Nigel; Cao, Ming; Wang, Menghan; Deng, Qiaolin; show more...; Hedlund, Eva; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Neurosciences

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