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@ARTICLE{Zimyanin:285016,
      author       = {Zimyanin, Vitaly and Dash, Banaja P and Simolka, Theresa
                      and Glaß, Hannes and Pal, Arun and Haidle, Felix and
                      Zarnack, Kathi and Verma, Riya and Khatri, Vivek and
                      Deppmann, Christopher and Zunder, Eli and Müller-McNicoll,
                      Michaela and Redemann, Stefanie and Hermann, Andreas},
      title        = {{C}ompartment-specific transcriptome of motor neurons
                      reveals impaired extracellular matrix signaling and
                      activated cell cycle kinases in {FUS}-{ALS}.},
      journal      = {Neurobiology of disease},
      volume       = {219},
      issn         = {0969-9961},
      address      = {[Amsterdam]},
      publisher    = {Elsevier},
      reportid     = {DZNE-2026-00142},
      pages        = {107268},
      year         = {2026},
      abstract     = {Mutations in FUSED IN SARCOMA (FUS) cause juvenile-onset
                      amyotrophic lateral sclerosis (ALS). Early pathogenesis of
                      FUS-ALS involves impaired transcription and splicing, DNA
                      damage response, and axonal degeneration. However, the
                      molecular pathophysiology and the link between somatic and
                      axonal phenotypes are still poorly understood. We evaluated
                      whether compartment-specific transcriptome differences could
                      distinguish and drive early axonal degeneration. We used
                      iPSC-derived motor neurons (MNs) coupled with microfluidic
                      approaches to generate RNA-sequencing profiles from axonal
                      and somatodendritic compartments. We demonstrate that the
                      axonal transcriptome is unique and distinct, with RNA
                      metabolism, extracellular secretion, and matrix disassembly
                      pathways particularly enriched in distal axonal
                      compartments. FUS mutation leads to changes in distinct
                      pathways that were clustered in only a few distinct
                      protein-protein interaction (PPI) networks. Somatodendritic
                      changes upon FUS mutation include WNT signaling,
                      mitochondrial, extracellular matrix (ECM)-, and
                      synapse-related functions. In contrast, analysis of the
                      axonal transcriptome in mutant MNs centers on the PLK1
                      pathway, mitochondrial gene expression, and regulation of
                      inflammation. Comparison to CLIP-seq data revealed a
                      significant enrichment for PLK1 and DNA replication pathways
                      in axons. PLK1 upregulation did not activate cell-cycle
                      re-entry but contributed to mutant MNs survival, and its
                      inhibition increased neuronal cell death. We propose that
                      upregulation of PLK1 represents an early event in the
                      pathogenesis of ALS and could act in response to DNA damage,
                      mitochondrial damage, and immune response activation in the
                      affected cells. Additionally, downregulation of ECM pathways
                      in the somatodendritic compartment and axons could explain
                      strongly compromised dynamics of axonal outgrowth. Overall,
                      we provide a novel valuable resource of the potential
                      targets and affected processes changed in the specific
                      compartments of FUS-ALS motor neurons.},
      keywords     = {Motor Neurons: metabolism / Motor Neurons: pathology /
                      RNA-Binding Protein FUS: genetics / RNA-Binding Protein FUS:
                      metabolism / Amyotrophic Lateral Sclerosis: genetics /
                      Amyotrophic Lateral Sclerosis: metabolism / Amyotrophic
                      Lateral Sclerosis: pathology / Transcriptome / Extracellular
                      Matrix: metabolism / Humans / Cell Cycle Proteins:
                      metabolism / Cell Cycle Proteins: genetics / Animals /
                      Signal Transduction: physiology / Axons: metabolism /
                      Induced Pluripotent Stem Cells: metabolism / Amyotrophic
                      lateral sclerosis (Other) / Axon degeneration (Other) /
                      Axonal outgrowth (Other) / Axonal transcriptome (Other) /
                      Cell cycle (Other) / DNA damage, PLK1 (Other) / ECM (Other)
                      / Induced pluripotent stem cells (Other) / RNA sequencing
                      (Other) / RNA-Binding Protein FUS (NLM Chemicals) / Cell
                      Cycle Proteins (NLM Chemicals) / FUS protein, human (NLM
                      Chemicals)},
      cin          = {AG Hermann},
      ddc          = {570},
      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:41525886},
      doi          = {10.1016/j.nbd.2026.107268},
      url          = {https://pub.dzne.de/record/285016},
}