Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson's disease.

Tytuł:: Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson's disease.
Autorzy:: Kamath T; Broad Institute of Harvard and MIT, Stanley Center for Psychiatric Research, Cambridge, MA, USA.; Harvard Graduate Program in Biophysics, Harvard University, Cambridge, MA, USA.
Abdulraouf A; Broad Institute of Harvard and MIT, Stanley Center for Psychiatric Research, Cambridge, MA, USA.
Burris SJ; Broad Institute of Harvard and MIT, Stanley Center for Psychiatric Research, Cambridge, MA, USA.
Langlieb J; Broad Institute of Harvard and MIT, Stanley Center for Psychiatric Research, Cambridge, MA, USA.
Gazestani V; Broad Institute of Harvard and MIT, Stanley Center for Psychiatric Research, Cambridge, MA, USA.
Nadaf NM; Broad Institute of Harvard and MIT, Stanley Center for Psychiatric Research, Cambridge, MA, USA.
Balderrama K; Broad Institute of Harvard and MIT, Stanley Center for Psychiatric Research, Cambridge, MA, USA.
Vanderburg C; Broad Institute of Harvard and MIT, Stanley Center for Psychiatric Research, Cambridge, MA, USA.
Macosko EZ; Broad Institute of Harvard and MIT, Stanley Center for Psychiatric Research, Cambridge, MA, USA. .; Massachusetts General Hospital, Department of Psychiatry, Boston, MA, USA. .
Źródło:: Nature neuroscience [Nat Neurosci] 2022 May; Vol. 25 (5), pp. 588-595. Date of Electronic Publication: 2022 May 05.
Typ publikacji:: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Publication: <2002->: New York, NY : Nature Publishing Group
Original Publication: New York, NY : Nature America Inc., c1998-
MeSH Terms:: Dopaminergic Neurons*/metabolism
Parkinson Disease*/genetics
Parkinson Disease*/metabolism
Genomics ; Humans ; Substantia Nigra
References:: EMBO J. 2016 Sep 15;35(18):1963-78. (PMID: 27354364)
Front Neuroanat. 2014 Dec 15;8:152. (PMID: 25565977)
Nat Rev Neurol. 2013 Nov;9(11):629-36. (PMID: 24126627)
Brain. 1999 Aug;122 ( Pt 8):1421-36. (PMID: 10430829)
J Mol Cell Biol. 2014 Feb;6(1):42-53. (PMID: 24431302)
Brain Res. 1987 May 12;411(1):144-50. (PMID: 2886180)
J Neurol Sci. 1997 Nov 6;152(1):73-83. (PMID: 9395128)
Neuroscience. 1994 Nov;63(1):47-56. (PMID: 7898660)
Nat Neurosci. 2021 Feb;24(2):276-287. (PMID: 33432193)
Nature. 2019 Sep;573(7772):61-68. (PMID: 31435019)
PLoS Comput Biol. 2015 Apr 17;11(4):e1004219. (PMID: 25885710)
Cell. 2017 Jun 15;169(7):1276-1290.e17. (PMID: 28602351)
Science. 2019 Mar 29;363(6434):1463-1467. (PMID: 30923225)
Nature. 2021 Oct;598(7879):214-219. (PMID: 34616064)
Cell. 2015 May 21;161(5):1202-1214. (PMID: 26000488)
Development. 2015 Jun 1;142(11):1918-36. (PMID: 26015536)
Cell. 2018 Aug 9;174(4):1015-1030.e16. (PMID: 30096299)
Biochem Biophys Res Commun. 1993 Dec 15;197(2):619-24. (PMID: 8267597)
Nat Genet. 2018 Jun;50(6):825-833. (PMID: 29785013)
Brain Res. 1990 Sep 3;526(2):303-7. (PMID: 2257487)
Cell. 2021 Feb 4;184(3):689-708.e20. (PMID: 33482083)
Nature. 2020 Oct;586(7828):262-269. (PMID: 32999462)
J Neurochem. 2016 Sep;138(5):746-57. (PMID: 27317935)
Brain. 1999 Aug;122 ( Pt 8):1437-48. (PMID: 10430830)
Nature. 2019 Jun;570(7761):332-337. (PMID: 31042697)
Lancet Neurol. 2019 Dec;18(12):1091-1102. (PMID: 31701892)
Nat Commun. 2015 Sep 10;6:8245. (PMID: 26356605)
Nat Methods. 2019 Dec;16(12):1289-1296. (PMID: 31740819)
Neurobiol Aging. 2003 Mar-Apr;24(2):197-211. (PMID: 12498954)
Trends Neurosci. 2020 Mar;43(3):155-169. (PMID: 32101709)
Science. 2020 Sep 11;369(6509):1318-1330. (PMID: 32913098)
Lancet. 2021 Jun 12;397(10291):2284-2303. (PMID: 33848468)
Neurobiol Dis. 2006 Aug;23(2):409-21. (PMID: 16753304)
Cell. 2016 Oct 6;167(2):566-580.e19. (PMID: 27716510)
Nat Neurosci. 2018 Oct;21(10):1350-1358. (PMID: 30250262)
Nat Cell Biol. 2009 Nov;11(11):1370-5. (PMID: 19801972)
Nature. 2019 Feb;566(7745):543-547. (PMID: 30747918)
Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22474-9. (PMID: 20007772)
PLoS One. 2018 Dec 26;13(12):e0209648. (PMID: 30586455)
Nat Commun. 2020 Aug 21;11(1):4183. (PMID: 32826893)
Cell. 2019 Jun 13;177(7):1873-1887.e17. (PMID: 31178122)
J Neurol Neurosurg Psychiatry. 1991 May;54(5):388-96. (PMID: 1865199)
Mol Neurodegener. 2017 Jan 19;12(1):9. (PMID: 28103901)
Ann Neurol. 2020 Jun;87(6):853-868. (PMID: 32167609)
Biochem Biophys Res Commun. 1997 Mar 17;232(2):418-21. (PMID: 9125193)
Curr Protoc. 2021 Mar;1(3):e90. (PMID: 33780170)
Brain. 1991 Oct;114 ( Pt 5):2283-301. (PMID: 1933245)
Nat Biotechnol. 2018 Jun;36(5):411-420. (PMID: 29608179)
Bioinformatics. 2021 May 17;37(7):963-967. (PMID: 32840568)
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50. (PMID: 16199517)
Sci Transl Med. 2018 Oct 17;10(463):. (PMID: 30333237)
Nat Genet. 2021 Mar;53(3):392-402. (PMID: 33589840)
Nat Biotechnol. 2021 Mar;39(3):313-319. (PMID: 33288904)
Neuron. 2005 Jul 7;47(1):29-41. (PMID: 15996546)
Brain. 2022 Apr 29;145(3):964-978. (PMID: 34919646)
Nature. 2019 Sep;573(7772):75-82. (PMID: 31316211)
Cell Rep. 2014 Aug 21;8(4):1018-25. (PMID: 25127144)
Science. 2019 May 17;364(6441):685-689. (PMID: 31097668)
Brain Pathol. 2015 Mar;25(2):121-35. (PMID: 24995389)
Acta Neuropathol. 2021 May;141(5):681-696. (PMID: 33609158)
Genome Biol. 2015 Dec 10;16:278. (PMID: 26653891)
Nat Genet. 2018 Apr;50(4):621-629. (PMID: 29632380)
Nat Commun. 2017 Jan 16;8:14049. (PMID: 28091601)
Nat Biotechnol. 2022 Apr;40(4):517-526. (PMID: 33603203)
Nat Genet. 2020 May;52(5):482-493. (PMID: 32341526)
Cell. 2015 May 21;161(5):1187-1201. (PMID: 26000487)
PLoS Genet. 2020 Jun 24;16(6):e1008868. (PMID: 32579581)
Grant Information:: DP2 AG058488 United States AG NIA NIH HHS; F30 AG069446 United States AG NIA NIH HHS; T32 GM007753 United States GM NIGMS NIH HHS; U01 MH124602 United States MH NIMH NIH HHS
Entry Date(s):: Date Created: 20220505 Date Completed: 20220510 Latest Revision: 20240214
Update Code:: 20240214
PubMed Central ID:: PMC9076534
DOI:: 10.1038/s41593-022-01061-1
PMID:: 35513515
: Czasopismo naukowe

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.
(© 2022. The Author(s).)

Comment in: Nat Neurosci. 2022 May;25(5):536-538. (PMID: 35513514)
Comment in: Nat Rev Neurol. 2022 Jul;18(7):381. (PMID: 35676370)
Comment in: Mov Disord. 2022 Aug;37(8):1610-1611. (PMID: 35766438)

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