Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson's disease.
Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson's disease.
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DOI：
10.1038/s41593-022-01061-1
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发表时间：
2022-05
影响因子：
25
通讯作者：
Macosko, Evan Z.
中科院分区：
文献类型：
--
作者：
Kamath, Tushar;Abdulraouf, Abdulraouf;Burris, S. J.;Langlieb, Jonah;Gazestani, Vahid;Nadaf, Naeem M.;Balderrama, Karol;Vanderburg, Charles;Macosko, Evan Z.
黑质致密部（SNpc）内多巴胺（DA）神经元的缺失是帕金森病（PD）的一个决定性病理标志。然而，与DA神经元易感性相关的分子特征尚未完全确定。在这里，我们开发了一种方案来丰富和转录分析PD患者和匹配对照的DA神经元，共采样387,483个细胞核，包括22,048个DA神经元图谱。我们确定了10个群体，并使用Slide-seq在SNpc中对每个群体进行了空间定位。单个亚型，以AGTR1基因的表达为标志，空间上局限于SNpc的腹侧层，在PD中非常容易丢失，并且TP53和NR2F2的靶点上调幅度最大，表明与变性相关的分子过程。同样的易感人群特别富集与PD相关的遗传风险，突出了细胞内在过程在决定DA神经元对PD相关变性的差异易感性方面的重要性。作者使用单细胞基因组学分析了数千个人类多巴胺神经元，并确定了一个独特的帕金森氏病易感人群，该人群富含帕金森氏病的遗传风险。
The loss of dopamine (DA) neurons within the substantia nigra pars compacta (SNpc) is a defining pathological hallmark of Parkinson’s disease (PD). Nevertheless, the molecular features associated with DA neuron vulnerability have not yet been fully identified. Here, we developed a protocol to enrich and transcriptionally profile DA neurons from patients with PD and matched controls, sampling a total of 387,483 nuclei, including 22,048 DA neuron profiles. We identified ten populations and spatially localized each within the SNpc using Slide-seq. A single subtype, marked by the expression of the gene AGTR1 and spatially confined to the ventral tier of SNpc, was highly susceptible to loss in PD and showed the strongest upregulation of targets of TP53 and NR2F2, nominating molecular processes associated with degeneration. This same vulnerable population was specifically enriched for the heritable risk associated with PD, highlighting the importance of cell-intrinsic processes in determining the differential vulnerability of DA neurons to PD-associated degeneration. The authors used single-cell genomics to profile thousands of human dopamine neurons and identify one uniquely Parkinson’s disease-susceptible population, which was enriched for genetic risk for Parkinson’s disease.
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影响因子：
30.8
作者：
Finucane HK;Reshef YA;Anttila V;Slowikowski K;Gusev A;Byrnes A;Gazal S;Loh PR;Lareau C;Shoresh N;Genovese G;Saunders A;Macosko E;Pollack S;Brainstorm Consortium;Perry JRB;Buenrostro JD;Bernstein BE;Raychaudhuri S;McCarroll S;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
25
作者：
Fu H;Hardy J;Duff KE
通讯作者：
Duff KE
DOI：
10.1073/pnas.0912193106
发表时间：
2009-12-29
影响因子：
11.1
作者：
Chung, Chee Yeun;Koprich, James B.;Isacson, Ole
通讯作者：
Isacson, Ole
影响因子：
17.1
作者：
Fonseka CY;Rao DA;Teslovich NC;Korsunsky I;Hannes SK;Slowikowski K;Gurish MF;Donlin LT;Lederer JA;Weinblatt ME;Massarotti EM;Coblyn JS;Helfgott SM;Todd DJ;Bykerk VP;Karlson EW;Ermann J;Lee YC;Brenner MB;Raychaudhuri S
通讯作者：
Raychaudhuri S
影响因子：
2.9
作者：
Brichta L;Greengard P
通讯作者：
Greengard P