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000285016 1001_ $$0P:(DE-HGF)0$$aZimyanin, Vitaly$$b0$$eFirst author
000285016 245__ $$aCompartment-specific transcriptome of motor neurons reveals impaired extracellular matrix signaling and activated cell cycle kinases in FUS-ALS.
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000285016 520__ $$aMutations 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.
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000285016 650_7 $$2Other$$aAmyotrophic lateral sclerosis
000285016 650_7 $$2Other$$aAxon degeneration
000285016 650_7 $$2Other$$aAxonal outgrowth
000285016 650_7 $$2Other$$aAxonal transcriptome
000285016 650_7 $$2Other$$aCell cycle
000285016 650_7 $$2Other$$aDNA damage, PLK1
000285016 650_7 $$2Other$$aECM
000285016 650_7 $$2Other$$aInduced pluripotent stem cells
000285016 650_7 $$2Other$$aRNA sequencing
000285016 650_7 $$2NLM Chemicals$$aRNA-Binding Protein FUS
000285016 650_7 $$2NLM Chemicals$$aCell Cycle Proteins
000285016 650_7 $$2NLM Chemicals$$aFUS protein, human
000285016 650_2 $$2MeSH$$aMotor Neurons: metabolism
000285016 650_2 $$2MeSH$$aMotor Neurons: pathology
000285016 650_2 $$2MeSH$$aRNA-Binding Protein FUS: genetics
000285016 650_2 $$2MeSH$$aRNA-Binding Protein FUS: metabolism
000285016 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: genetics
000285016 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: metabolism
000285016 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: pathology
000285016 650_2 $$2MeSH$$aTranscriptome
000285016 650_2 $$2MeSH$$aExtracellular Matrix: metabolism
000285016 650_2 $$2MeSH$$aHumans
000285016 650_2 $$2MeSH$$aCell Cycle Proteins: metabolism
000285016 650_2 $$2MeSH$$aCell Cycle Proteins: genetics
000285016 650_2 $$2MeSH$$aAnimals
000285016 650_2 $$2MeSH$$aSignal Transduction: physiology
000285016 650_2 $$2MeSH$$aAxons: metabolism
000285016 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: metabolism
000285016 7001_ $$aDash, Banaja P$$b1
000285016 7001_ $$aSimolka, Theresa$$b2
000285016 7001_ $$aGlaß, Hannes$$b3
000285016 7001_ $$aPal, Arun$$b4
000285016 7001_ $$aHaidle, Felix$$b5
000285016 7001_ $$aZarnack, Kathi$$b6
000285016 7001_ $$aVerma, Riya$$b7
000285016 7001_ $$aKhatri, Vivek$$b8
000285016 7001_ $$aDeppmann, Christopher$$b9
000285016 7001_ $$aZunder, Eli$$b10
000285016 7001_ $$aMüller-McNicoll, Michaela$$b11
000285016 7001_ $$aRedemann, Stefanie$$b12
000285016 7001_ $$0P:(DE-2719)2811732$$aHermann, Andreas$$b13$$eLast author$$udzne
000285016 773__ $$0PERI:(DE-600)1471408-5$$a10.1016/j.nbd.2026.107268$$gVol. 219, p. 107268 -$$p107268$$tNeurobiology of disease$$v219$$x0969-9961$$y2026
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