ALS-associated VRK1 R321C mutation causes proteostatic imbalance and mitochondrial defects in iPSC-derived motor neurons

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Oliveira, D. ; Assoni, A. F. ; Alves, L. M. ; Sakugawa, A. ; Melo, U. S. ; Teles eSilva, A. L. ; Sertie, A. L. ; Caires, L. C. ; Goulart, E. ; Ghirotto, B. ; Carvalho, V. M. ; Ferrari, M. R. ; Zatz, M.

• Tipo de documento: Artigo Científico
• Fonte: Neurobiology of Disease; v. 198, p. 8-pg., 2024-05-31.

Resumo

Vaccinia-related kinase 1 ( VRK1 ) is a gene which has been implicated in the pathological process of a broad range of neurodevelopmental disorders as well as neuropathies, such as Amyotrophic Lateral Sclerosis (ALS). Here we report a family presenting ALS in an autosomal recessive mode of inheritance, segregating with a homozygous missense mutation located in VRK1 gene (p.R321C; Arg321Cys). Proteomic analyses from iPSCderived motor neurons identified 720 proteins eligible for subsequent investigation, and our exploration of protein profiles revealed significant enrichments in pathways such as mTOR signaling, E2F, MYC targets, DNA repair response, cell proliferation and energetic metabolism. Functional studies further validated such alterations, showing that affected motor neurons presented decreased levels of global protein output, ER stress and downregulation of mTOR signaling. Mitochondrial alterations also pointed to decreased reserve capacity and increased non-mitochondrial oxygen consumption. Taken together, our results present the main pathological alterations associated with VRK1 mutation in ALS. (AU)

• Processo FAPESP: 13/08028-1 - CEGH-CEL - Centro de Estudos do Genoma Humano e de Células-Tronco
• Beneficiário: Mayana Zatz
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 21/05194-4 - Estudos sobre a fisiopatologia da Esclerose Lateral Amiotrófica tipo 8 através de modelos de células-tronco pluripotentes induzidas
• Beneficiário: Danyllo Felipe de Oliveira
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado