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@ARTICLE{Szewczyk:280968,
author = {Szewczyk, Barbara and Zimyanin, Vitaly and Japtok, Julia
and Held, Aaron and Pal, Arun and Großmann, Dajana and
Glaß, Hannes and Jürs, Alexandra V and Dash, Banaja P and
Bak, Maciek and Naumann, Marcel and Hartmann, Christiane and
Kuksenko, Olena and Günther, René and Kao, Tzu-Ting and
Sameith, Katrin and Dahl, Andreas and Sterneckert, Jared and
Aronica, Eleonora and Shneider, Neil A and Büttner, Andreas
and Catanese, Alberto and Phatnani, Hemali and Kipp, Markus
and Wainger, Brian J and Goswami, Anand and Hermann,
Andreas},
title = {{A}ctivation of polo-like kinase 1 correlates with
selective motor neuron vulnerability in familial {ALS}.},
journal = {Cell reports},
volume = {44},
number = {9},
issn = {2211-1247},
address = {Maryland Heights, MO},
publisher = {Cell Press},
reportid = {DZNE-2025-01050},
pages = {116113},
year = {2025},
abstract = {Mutations in the Fused in Sarcoma (FUS) gene cause familial
amyotrophic lateral sclerosis (ALS), characterized by
selective degeneration of spinal motor neurons (sMNs) with
relative sparing of cortical neurons (CNs). The mechanisms
underlying this cell-type vulnerability remain unclear.
Here, we compare CNs and sMNs derived from FUS-ALS models to
assess differential responses to FUS mutations. We find that
CNs are less affected than sMNs in DNA damage repair, axonal
organelle trafficking, and stress granule dynamics. RNA
sequencing (RNA-seq) reveals distinct transcriptomic
signatures, with sMNs uniquely activating DNA damage
responses involving cell cycle regulators, particularly
polo-like kinase 1 (PLK1). PLK1 is highly expressed in sMNs
but not CNs, correlating with greater nuclear FUS loss and
splicing defects in sMNs. Cross-comparison with other
familial ALS RNA-seq datasets highlights PLK1 upregulation
as a shared molecular feature. These findings identify
intrinsic differences between CNs and sMNs in FUS-ALS and
suggest PLK1 as a potential driver of sMN vulnerability.},
keywords = {CP: Molecular biology (Other) / CP: Neuroscience (Other) /
DNA damage response (Other) / FUS loss of function (Other) /
FUS-ALS (Other) / PLK1 (Other) / neurodegeneration (Other) /
polo-like kinase 1 (Other) / selective vulnerability (Other)
/ transcriptomics (Other)},
cin = {AG Hermann},
ddc = {610},
cid = {I:(DE-2719)1511100},
pnm = {353 - Clinical and Health Care Research (POF4-353)},
pid = {G:(DE-HGF)POF4-353},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40857153},
doi = {10.1016/j.celrep.2025.116113},
url = {https://pub.dzne.de/record/280968},
}