Different gene expression profiles in iPSC-derived motor neurons from ALS8 patients with variable clinical courses suggest mitigating pathways for neurodegeneration
| Autor: | Danyllo Oliveira, Livia Luz, Felipe de Souza Leite, Carolini Kaid, Oswaldo Keith Okamoto, Mayana Zatz, Uirá Souto Melo, Thalita Figueiredo, Luiz Carlos de Caires, Andréa L. Sertié, Sergio Verjovski-Almeida, Ernesto Goulart, Murilo S. Amaral, David A. Morales-Vicente, Miguel Mitne-Neto, Claudia D. C. Navarro, Joyce Esposito, Luciana M Alves |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Induced Pluripotent Stem Cells Vesicular Transport Proteins Biology Endoplasmic Reticulum 03 medical and health sciences 0302 clinical medicine Gene expression Genetics medicine Humans RNA-Seq Amyotrophic lateral sclerosis Molecular Biology Gene Genetics (clinical) Aged 030304 developmental biology Motor Neurons 0303 health sciences Amyotrophic Lateral Sclerosis Neurodegeneration Cell Differentiation General Medicine Middle Aged Motor neuron VAPB medicine.disease Mitochondria Cell biology Gene expression profiling Oxidative Stress Proteostasis medicine.anatomical_structure Gene Expression Regulation Nerve Degeneration Female 030217 neurology & neurosurgery |
| Zdroj: | Human Molecular Genetics. 29:1465-1475 |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddaa069 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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