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

Oliveira D, Assoni AF, Alves LM, Sakugawa A, Melo US, Teles e Silva AL, Sertie AL, Caires LC, Goulart E, Ghirotto B, Carvalho VM, Ferrari MR, Zatz M (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Neurobiology of Disease Elsevier

Book Volume: 198

Article Number: 106540

DOI: 10.1016/j.nbd.2024.106540

Abstract

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.

Authors with CRIS profile

Bruno Ghirotto Nunes Professur für Stammzell-Modelle seltener neuraler Erkrankungen

Involved external institutions

University of São Paulo / Universidade de São Paulo (USP) BR Brazil (BR) Hospital Israelita Albert Einstein BR Brazil (BR) Max-Planck-Institut für molekulare Genetik / Max Planck Institute for Molecular Genetics DE Germany (DE)

How to cite

APA:

Oliveira, D., Assoni, A.F., Alves, L.M., Sakugawa, A., Melo, U.S., Teles e Silva, A.L.,... Zatz, M. (2024). ALS-associated VRK1 R321C mutation causes proteostatic imbalance and mitochondrial defects in iPSC-derived motor neurons. Neurobiology of Disease, 198. https://doi.org/10.1016/j.nbd.2024.106540

MLA:

Oliveira, D., et al. "ALS-associated VRK1 R321C mutation causes proteostatic imbalance and mitochondrial defects in iPSC-derived motor neurons." Neurobiology of Disease 198 (2024).

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