Journal Article

DZNE-2025-01050

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Activation of polo-like kinase 1 correlates with selective motor neuron vulnerability in familial ALS.

Szewczyk, B.Extern* ; Zimyanin, V. ; Japtok, J. ; Held, A. ; Pal, A. ; Großmann, D. ; Glaß, H. ; Jürs, A. V. ; Dash, B. P. ; Bak, M. ; Naumann, M. ; Hartmann, C. ; Kuksenko, O. ; Günther, R.Extern* ; Kao, T.-T. ; Sameith, K. ; Dahl, A. ; Sterneckert, J. ; Aronica, E. ; Shneider, N. A. ; Büttner, A. ; Catanese, A.Extern* ; Phatnani, H. ; Kipp, M.DZNE* ; Wainger, B. J. ; Goswami, A. ; Hermann, A. (Last author)DZNE*

2025
Cell Press Maryland Heights, MO

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Please use a persistent id in citations: doi:10.1016/j.celrep.2025.116113

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.

Keyword(s): CP: Molecular biology ; CP: Neuroscience ; DNA damage response ; FUS loss of function ; FUS-ALS ; PLK1 ; neurodegeneration ; polo-like kinase 1 ; selective vulnerability ; transcriptomics

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Contributing Institute(s):

1. Translational Neurodegeneration (AG Hermann)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2025

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