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

Author(s):Show less -

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.

• Document type: Journal article
• Source: Neurobiology of Disease; v. 198, p. 8-pg., 2024-05-31.

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 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)

• FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
• Grantee: Mayana Zatz
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 21/05194-4 - Studies on Amyotrophic Lateral Sclerosis type 8 physiopathology through induced pluripotent stem cell models
• Grantee: Danyllo Felipe de Oliveira
• Support Opportunities: Scholarships in Brazil - Post-Doctoral