2. Academic Validation
  3. Activation of polo-like kinase 1 correlates with selective motor neuron vulnerability in familial ALS

Activation of polo-like kinase 1 correlates with selective motor neuron vulnerability in familial ALS

  • Cell Rep. 2025 Aug 25;44(9):116113. doi: 10.1016/j.celrep.2025.116113.
Barbara Szewczyk 1,  Vitaly Zimyanin 2,  Julia Japtok 3,  Aaron Held 4,  Arun Pal 5,  Dajana Großmann 1,  Hannes Glaß 1,  Alexandra V Jürs 1,  Banaja P Dash 1,  Maciek Bak 6,  Marcel Naumann 1,  Christiane Hartmann 1,  Olena Kuksenko 7,  René Günther 3,  Tzu-Ting Kao 8,  Katrin Sameith 9,  Andreas Dahl 9,  Jared Sterneckert 10,  Eleonora Aronica 11,  Neil A Shneider 12,  Andreas Büttner 13,  Alberto Catanese 14,  Hemali Phatnani 7,  Markus Kipp 15,  Brian J Wainger 16,  Anand Goswami 8,  Andreas Hermann 17
Affiliations

Affiliations

  • 1 Translational Neurodegeneration Section "Albrecht Kossel", Department of Neurology, Rostock University Medical Center, Rostock, Germany.
  • 2 Department of Molecular Physiology and Biological Physics and Center for Membrane and Cell Physiology, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • 3 Department of Neurology, Technische Universität Dresden, Dresden, Germany.
  • 4 Department of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Boston, MA, USA.
  • 5 Department of Neurology, Technische Universität Dresden, Dresden, Germany; Dresden High Magnetic Field Laboratory (HLD-EMFL), Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 01328 Dresden, Germany.
  • 6 CORE, Krakow, Poland.
  • 7 Center for Genomics of Neurodegenerative Disease, New York Genome Center, New York, NY 10013, USA.
  • 8 Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA; Department of Neurology, Eleanor and Lou Gehrig ALS Center, Columbia University, New York, NY 10032, USA.
  • 9 DRESDEN-concept Genome Center, Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, 01307 Dresden, Germany.
  • 10 Centre for Regenerative Therapies TU Dresden, Technische Universität Dresden, Dresden, Germany; Medical Faculty Carl Gustav Carus of TU Dresden, Dresden, Germany.
  • 11 Department of (Neuro)Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands.
  • 12 Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA.
  • 13 Institute of Forensic Medicine, Rostock University Medical Center, 18055 Rostock, Germany.
  • 14 Institute of Anatomy and Cell Biology, Ulm University, 89081 Ulm, Germany.
  • 15 Institute for Anatomy, Rostock University Medical Center, Rostock, Germany; German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald, Rostock, Germany; Center for Transdisciplinary Neurosciences Rostock (CTNR), Rostock University Medical Center, Rostock, Germany.
  • 16 Department of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Boston, MA, USA; Department of Anesthesiology, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston MA 02114, USA; Broad Institute of Harvard University and MIT, Cambridge, MA 02142, USA.
  • 17 Translational Neurodegeneration Section "Albrecht Kossel", Department of Neurology, Rostock University Medical Center, Rostock, Germany; German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald, Rostock, Germany; Center for Transdisciplinary Neurosciences Rostock (CTNR), Rostock University Medical Center, Rostock, Germany. Electronic address: andreas.hermann@med.uni-rostock.de.
PMID: 40857153 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.

Keywords

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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