TY  - JOUR
AU  - Szewczyk, Barbara
AU  - Zimyanin, Vitaly
AU  - Japtok, Julia
AU  - Held, Aaron
AU  - Pal, Arun
AU  - Großmann, Dajana
AU  - Glaß, Hannes
AU  - Jürs, Alexandra V
AU  - Dash, Banaja P
AU  - Bak, Maciek
AU  - Naumann, Marcel
AU  - Hartmann, Christiane
AU  - Kuksenko, Olena
AU  - Günther, René
AU  - Kao, Tzu-Ting
AU  - Sameith, Katrin
AU  - Dahl, Andreas
AU  - Sterneckert, Jared
AU  - Aronica, Eleonora
AU  - Shneider, Neil A
AU  - Büttner, Andreas
AU  - Catanese, Alberto
AU  - Phatnani, Hemali
AU  - Kipp, Markus
AU  - Wainger, Brian J
AU  - Goswami, Anand
AU  - Hermann, Andreas
TI  - Activation of polo-like kinase 1 correlates with selective motor neuron vulnerability in familial ALS.
JO  - Cell reports
VL  - 44
IS  - 9
SN  - 2211-1247
CY  - Maryland Heights, MO
PB  - Cell Press
M1  - DZNE-2025-01050
SP  - 116113
PY  - 2025
AB  - 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.
KW  - CP: Molecular biology (Other)
KW  - CP: Neuroscience (Other)
KW  - DNA damage response (Other)
KW  - FUS loss of function (Other)
KW  - FUS-ALS (Other)
KW  - PLK1 (Other)
KW  - neurodegeneration (Other)
KW  - polo-like kinase 1 (Other)
KW  - selective vulnerability (Other)
KW  - transcriptomics (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:40857153
DO  - DOI:10.1016/j.celrep.2025.116113
UR  - https://pub.dzne.de/record/280968
ER  -