| Full text | |
| Author(s): Show less - |
Oliveira, Danyllo
[1]
;
Morales-Vicente, David A.
[2, 3]
;
Amaral, Murilo S.
[3]
;
Luz, Livia
[4]
;
Sertie, Andrea L.
[5]
;
Leite, Felipe S.
[1]
;
Navarro, Claudia
[6]
;
Kaid, Carolini
[1]
;
Esposito, Joyce
[1]
;
Goulart, Ernesto
[1]
;
Caires, Luiz
[1]
;
Alves, Luciana M.
[1]
;
Melo, Uira S.
[1]
;
Figueiredo, Thalita
[1, 7]
;
Mitne-Neto, Miguel
[8]
;
Okamoto, Oswaldo K.
[1]
;
Verjovski-Almeida, Sergio
[2, 3]
;
Zatz, Mayana
[1]
Total Authors: 18
|
| Affiliation: | [1] Univ Sao Paulo, Human Genome & Stem Cell Res Ctr, Inst Biosci, Dept Genet & Evolutionary Biol, Rua Matao 106, Cidade Univ, BR-05508090 Sao Paulo, SP - Brazil
[2] Univ Sao Paulo, Inst Chem, Dept Biochem, BR-05508000 Sao Paulo - Brazil
[3] Inst Butantan, Lab Gene Express Eukaryotes, Ave Vital Brasil 1500, Predio 55, BR-05503900 Sao Paulo, SP - Brazil
[4] Univ Sao Paulo, Inst Biomed Sci, Lab DNA Repair, BR-05508000 Sao Paulo - Brazil
[5] Hosp Albert Einstein, BR-05652900 Sao Paulo - Brazil
[6] Univ Estadual Campinas, Fac Med Sci, Dept Clin Pathol, BR-13083887 Campinas - Brazil
[7] Univ Fed Alagoas, Fac Med, BR-57972900 Maceio, Alagoas - Brazil
[8] Res & Dev, Fleury Grp, BR-04344070 Sao Paulo, SP - Brazil
Total Affiliations: 8
|
| Document type: | Journal article |
| Source: | Human Molecular Genetics; v. 29, n. 9, p. 1465-1475, MAY 1 2020. |
| Web of Science Citations: | 2 |
| Abstract | |
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. (AU) | |
| FAPESP's process: | 15/14821-1 - Development of functional hepatic by-pass using iPSCs-derived cells |
| Grantee: | Ernesto da Silveira Goulart Guimarães |
| Support Opportunities: | Scholarships in Brazil - Doctorate |
| FAPESP's process: | 17/16283-2 - Development of tissue bioengineering techniques for the functional reconstruction of ex vivo iPSC cell livers |
| Grantee: | Luiz Carlos de Caires Júnior |
| Support Opportunities: | Scholarships in Brazil - Post-Doctoral |