Different gene expression profiles in iPSC-derived motor neurons from ALS8 patients with variable clinical courses suggest mitigating pathways for neurodegeneration.

Autor:	Oliveira D; Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, University of São Paulo, São Paulo 05508-090, Brazil., Morales-Vicente DA; Laboratory of Gene Expression in Eukaryotes, Instituto Butantan, São Paulo 05503-900, Brazil.; Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo 05508-000, Brazil., Amaral MS; Laboratory of Gene Expression in Eukaryotes, Instituto Butantan, São Paulo 05503-900, Brazil., Luz L; Laboratory of DNA Repair, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil., Sertié AL; Hospital Albert Einstein, São Paulo 05652-900, Brazil., Leite FS; Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, University of São Paulo, São Paulo 05508-090, Brazil., Navarro C; Department of Clinical Pathology, Faculty of Medical Sciences, University of Campinas, Campinas 13083-887, Brazil., Kaid C; Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, University of São Paulo, São Paulo 05508-090, Brazil., Esposito J; Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, University of São Paulo, São Paulo 05508-090, Brazil., Goulart E; Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, University of São Paulo, São Paulo 05508-090, Brazil., Caires L; Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, University of São Paulo, São Paulo 05508-090, Brazil., Alves LM; Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, University of São Paulo, São Paulo 05508-090, Brazil., Melo US; Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, University of São Paulo, São Paulo 05508-090, Brazil., Figueiredo T; Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, University of São Paulo, São Paulo 05508-090, Brazil.; Faculty of Medicine, Federal University of Alagoas, Maceió 57972-900, Brazil., Mitne-Neto M; Fleury Group, Research and Development. São Paulo, São Paulo 04344-070, Brazil., Okamoto OK; Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, University of São Paulo, São Paulo 05508-090, Brazil., Verjovski-Almeida S; Laboratory of Gene Expression in Eukaryotes, Instituto Butantan, São Paulo 05503-900, Brazil.; Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo 05508-000, Brazil., Zatz M; Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, University of São Paulo, São Paulo 05508-090, Brazil.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2020 Jun 03; Vol. 29 (9), pp. 1465-1475.
DOI:	10.1093/hmg/ddaa069
Abstrakt:	Amyotrophic lateral sclerosis type 8 (ALS8) is an autosomal dominant form of ALS, which is caused by pathogenic variants in the VAPB gene. Here we investigated five ALS8 patients, classified as 'severe' and 'mild' from a gigantic Brazilian kindred, carrying the same VAPB mutation but displaying different clinical courses. Copy number variation and whole exome sequencing analyses in such individuals ruled out previously described genetic modifiers of pathogenicity. After deriving induced pluripotent stem cells (iPSCs) for each patient (N = 5) and controls (N = 3), motor neurons were differentiated, and high-throughput RNA-Seq gene expression measurements were performed. Functional cell death and oxidative metabolism assays were also carried out in patients' iPSC-derived motor neurons. The degree of cell death and mitochondrial oxidative metabolism were similar in iPSC-derived motor neurons from mild patients and controls and were distinct from those of severe patients. Similar findings were obtained when RNA-Seq from such cells was performed. Overall, 43 genes were upregulated and 66 downregulated in the two mild ALS8 patients when compared with severe ALS8 individuals and controls. Interestingly, significantly enriched pathways found among differentially expressed genes, such as protein translation and protein targeting to the endoplasmic reticulum (ER), are known to be associated with neurodegenerative processes. Taken together, the mitigating mechanisms here presented appear to maintain motor neuron survival by keeping translational activity and protein targeting to the ER in such cells. As ALS8 physiopathology has been associated with proteostasis mechanisms in ER-mitochondria contact sites, such differentially expressed genes appear to relate to the bypass of VAPB deficiency. (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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