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

• Published in: Neurobiology of disease Vol. 198; p. 106540
• Main Authors: Oliveira, D., Assoni, A.F., Alves, L.M., Sakugawa, A., Melo, U.S., Teles e Silva, A.L., Sertie, A.L., Caires, L.C., Goulart, E., Ghirotto, B., Carvalho, V.M., Ferrari, M.R., Zatz, M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2024; Elsevier
• Subjects: Adult; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Autosomal recessive inheritance; Female; Humans; Induced Pluripotent Stem Cells - metabolism; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Male; Middle Aged; Mitochondria - genetics; Mitochondria - metabolism; Mitochondria - pathology; Motor Neurons - metabolism; Motor Neurons - pathology; Mutation, Missense; Neurogenetics; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proteostasis - genetics; VRK1; Amyotrophic lateral sclerosis; VRK1; Neurogenetics; Autosomal recessive inheritance
• ISSN: 0969-9961; 1095-953X; 1095-953X
• DOI: 10.1016/j.nbd.2024.106540

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 iPSC-derived 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. •VRK1 is a serine-threonine kinase associated with multiple cellular pathways such as DNA repair, transcription and cell proliferation;•Mutations in VRK1 gene have been associated with severalneurological conditions both in neurodevelopmental and in neurodegeneration phenotypes;•A homozygous mutation in VRK1 gene (p.VRK1 R321C) has been described in a family with early onset Amyotrophic Lateral Sclerosis;•iPSC-derived motor neurons from affected patients presented multiple cellular phenotypes, such as depletion of mitochondrial activity, increased ER stress and protein translation arrest.