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Activation of polo-like kinase 1 expression in spinal motor neurons as vulnerability factor of spinal motor neurons in FUS- and other fALS

ABSTRACT: FUS ALS seems to preferentially affect sMNs, and cognitive dysfunction in FUS ALS is rare. Considering this, we wanted to analyze if cortical neurons behave differently than spinal motor neurons in response to FUS mutations. For this, we used cortical neurons derived from isogenic human induced pluripotent stem cells (hiPSCs) in which either WT or NLS mutant FUS P525L was tagged with eGFP using CRISPR/Cas9 and systematically compared them to sMNs of the identical iPSCs. Phenotypically, mutant FUS cortical neurons showed less impairment of FUS recruitment to DNA damage sites compared to mutant sMNs and less signs of DNA damage, which were similarly found in post mortem tissue. To advance our understanding of finding different molecular mechanisms and pathways related to FUS mutations in ALS disease, we have performed RNA sequencing of FUS ALS cortical and spinal motor neurons and our results revealed basic differences in their transcriptomes. Alternative splicing events in spinal motor neurons were different from cortical neurons also pointing towards DNA damage in FUS ALS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272827 | GEO | 2024/08/27

REPOSITORIES: GEO

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A low level of expression of C-terminally truncated human FUS causes extensive changes in the spinal cord transcriptome of asymptomatic transgenic mice

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