A molecular census of midbrain dopaminergic neurons in Parkinsons disease

Midbrain dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) project widely throughout the central nervous system, playing critical roles in voluntary movements, reward processing, and working memory. Many of these neurons are highly sensitive to neurodegeneration in Parkinson’s Disease (PD), and their loss correlates strongly with the pathognomonic symptoms. To characterize these populations molecularly, we developed a protocol to enrich and transcriptionally profile DA neuron nuclei from postmortem human SNpc of both PD patients and matched controls. We identified a total of ten distinct populations, including one that was primate-specific. A single subtype, marked by the gene AGTR1, was highly susceptible to degeneration, and was enriched for expression of genes associated with PD in genetic studies, suggesting many risk loci act within this subtype to influence its neurodegeneration. The AGTR1 subtype also showed the strongest upregulation of TP53 and its downstream targets, nominating a potential pathway of degeneration in vivo. The transcriptional characterization of differentially disease-vulnerable DA neurons in the SNpc will inform the development of laboratory models, enable the nomination of novel disease biomarkers, and guide further studies of pathogenic disease mechanisms.中脑多巴胺（dopamine, DA）神经元广泛投射至中枢神经系统，在自主运动、奖赏处理与工作记忆中发挥关键作用。黑质致密部（substantia nigra pars compacta, SNpc）的多巴胺神经元中，多数对帕金森病（Parkinson’s Disease, PD）引发的神经退行性变高度敏感，其丢失与该病的特征性临床症状密切相关。为从分子层面表征这群神经元的群体特征，我们开发了一套实验方案，可从帕金森病患者及匹配对照的死后人类黑质致密部样本中富集多巴胺神经元细胞核并开展转录组分析。本研究共鉴定出10种不同的神经元亚型，其中1种为灵长类特异性亚型。以基因AGTR1为标志物的单一亚型对神经退行性变易感性极高，且在遗传学研究中显著富集了与帕金森病相关的基因表达特征，提示诸多疾病风险位点可通过该亚型影响其神经退行性进程。该AGTR1阳性亚型同时表现出TP53及其下游靶基因的最强表达上调，为体内神经退行性变的潜在通路提供了候选方向。对黑质致密部中疾病易感性存在差异的多巴胺神经元进行转录组表征，将有助于实验室疾病模型的开发、新型疾病生物标志物的筛选，并为进一步研究致病机制提供指导。