TY - JOUR
T1 - Single-cell dissection of the human motor and prefrontal cortices in ALS and FTLD
AU - Pineda, S. Sebastian
AU - Lee, Hyeseung
AU - Ulloa-Navas, Maria J.
AU - Linville, Raleigh M.
AU - Garcia, Francisco J.
AU - Galani, Kyriakitsa
AU - Engelberg-Cook, Erica
AU - Castanedes, Monica C.
AU - Fitzwalter, Brent E.
AU - Pregent, Luc J.
AU - Gardashli, Mahammad E.
AU - DeTure, Michael
AU - Vera-Garcia, Diana V.
AU - Hucke, Andre T.S.
AU - Oskarsson, Bjorn E.
AU - Murray, Melissa E.
AU - Dickson, Dennis W.
AU - Heiman, Myriam
AU - Belzil, Veronique V.
AU - Kellis, Manolis
N1 - Publisher Copyright:
© 2024 Elsevier Inc.
PY - 2024/4/11
Y1 - 2024/4/11
N2 - Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) share many clinical, pathological, and genetic features, but a detailed understanding of their associated transcriptional alterations across vulnerable cortical cell types is lacking. Here, we report a high-resolution, comparative single-cell molecular atlas of the human primary motor and dorsolateral prefrontal cortices and their transcriptional alterations in sporadic and familial ALS and FTLD. By integrating transcriptional and genetic information, we identify known and previously unidentified vulnerable populations in cortical layer 5 and show that ALS- and FTLD-implicated motor and spindle neurons possess a virtually indistinguishable molecular identity. We implicate potential disease mechanisms affecting these cell types as well as non-neuronal drivers of pathogenesis. Finally, we show that neuron loss in cortical layer 5 tracks more closely with transcriptional identity rather than cellular morphology and extends beyond previously reported vulnerable cell types.
AB - Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) share many clinical, pathological, and genetic features, but a detailed understanding of their associated transcriptional alterations across vulnerable cortical cell types is lacking. Here, we report a high-resolution, comparative single-cell molecular atlas of the human primary motor and dorsolateral prefrontal cortices and their transcriptional alterations in sporadic and familial ALS and FTLD. By integrating transcriptional and genetic information, we identify known and previously unidentified vulnerable populations in cortical layer 5 and show that ALS- and FTLD-implicated motor and spindle neurons possess a virtually indistinguishable molecular identity. We implicate potential disease mechanisms affecting these cell types as well as non-neuronal drivers of pathogenesis. Finally, we show that neuron loss in cortical layer 5 tracks more closely with transcriptional identity rather than cellular morphology and extends beyond previously reported vulnerable cell types.
KW - ALS
KW - Betz cell
KW - FTLD
KW - frontotemporal dementia
KW - motor neuron
KW - neurodegeneration
KW - single cell
KW - spindle neuron
KW - von Economo
UR - http://www.scopus.com/inward/record.url?scp=85189567812&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85189567812&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2024.02.031
DO - 10.1016/j.cell.2024.02.031
M3 - Article
C2 - 38521060
AN - SCOPUS:85189567812
SN - 0092-8674
VL - 187
SP - 1971-1989.e16
JO - Cell
JF - Cell
IS - 8
ER -