%0 Journal Article
%A Zimyanin, Vitaly
%A Dash, Banaja P
%A Simolka, Theresa
%A Glaß, Hannes
%A Pal, Arun
%A Haidle, Felix
%A Zarnack, Kathi
%A Verma, Riya
%A Khatri, Vivek
%A Deppmann, Christopher
%A Zunder, Eli
%A Müller-McNicoll, Michaela
%A Redemann, Stefanie
%A Hermann, Andreas
%T Compartment-specific transcriptome of motor neurons reveals impaired extracellular matrix signaling and activated cell cycle kinases in FUS-ALS.
%J Neurobiology of disease
%V 219
%@ 0969-9961
%C [Amsterdam]
%I Elsevier
%M DZNE-2026-00142
%P 107268
%D 2026
%X 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.
%K Motor Neurons: metabolism
%K Motor Neurons: pathology
%K RNA-Binding Protein FUS: genetics
%K RNA-Binding Protein FUS: metabolism
%K Amyotrophic Lateral Sclerosis: genetics
%K Amyotrophic Lateral Sclerosis: metabolism
%K Amyotrophic Lateral Sclerosis: pathology
%K Transcriptome
%K Extracellular Matrix: metabolism
%K Humans
%K Cell Cycle Proteins: metabolism
%K Cell Cycle Proteins: genetics
%K Animals
%K Signal Transduction: physiology
%K Axons: metabolism
%K Induced Pluripotent Stem Cells: metabolism
%K Amyotrophic lateral sclerosis (Other)
%K Axon degeneration (Other)
%K Axonal outgrowth (Other)
%K Axonal transcriptome (Other)
%K Cell cycle (Other)
%K DNA damage, PLK1 (Other)
%K ECM (Other)
%K Induced pluripotent stem cells (Other)
%K RNA sequencing (Other)
%K RNA-Binding Protein FUS (NLM Chemicals)
%K Cell Cycle Proteins (NLM Chemicals)
%K FUS protein, human (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:41525886
%R 10.1016/j.nbd.2026.107268
%U https://pub.dzne.de/record/285016