Absence of R‐Ras1 and R‐Ras2 causes mitochondrial alterations that trigger axonal degeneration in a hypomyelinating disease model. Issue 3 (3rd October 2020)

• Record Type: Journal Article
• Authors: Alcover‐Sanchez, Berta; Garcia‐Martin, Gonzalo; Escudero‐Ramirez, Juan; Gonzalez‐Riano, Carolina; Lorenzo, Paz; Gimenez‐Cassina, Alfredo; Formentini, Laura; de la Villa‐Polo, Pedro; Pereira, Marta P.; Wandosell, Francisco; Cubelos, Beatriz
• Is Part Of: Glia. Volume 69:Issue 3(2021)
• Page Start: 619
• Page End: 637
• Publication Date: 2020-10-03
• Subjects: mitochondria -- multiple sclerosis -- myelin -- neurodegeneration -- oligodendrocyte -- R‐Ras; Neuroglia -- Periodicals; Neurology -- Periodicals; 611.0188
• DOI: 10.1002/glia.23917
• Languages: English
• ISSNs: 0894-1491

Abstract

Abstract: Fast synaptic transmission in vertebrates is critically dependent on myelin for insulation and metabolic support. Myelin is produced by oligodendrocytes (OLs) that maintain multilayered membrane compartments that wrap around axonal fibers. Alterations in myelination can therefore lead to severe pathologies such as multiple sclerosis. Given that hypomyelination disorders have complex etiologies, reproducing clinical symptoms of myelin diseases from a neurological perspective in animal models has been difficult. We recently reported that R‐Ras1 −/− and/or R‐Ras2 −/− mice, which lack GTPases essential for OL survival and differentiation processes, present different degrees of hypomyelination in the central nervous system with a compounded hypomyelination in double knockout ( DKO ) mice. Here, we discovered that the loss of R‐Ras1 and/or R‐Ras2 function is associated with aberrant myelinated axons with increased numbers of mitochondria, and a disrupted mitochondrial respiration that leads to increased reactive oxygen species levels. Consequently, aberrant myelinated axons are thinner with cytoskeletal phosphorylation patterns typical of axonal degeneration processes, characteristic of myelin diseases. Although we observed different levels of hypomyelination in a single mutant mouse, the combined loss of function in DKO mice lead to a compromised axonal integrity, triggering the loss of visual function. Our findings demonstrate that the loss of R‐Ras function reproduces several characteristics of hypomyelinating diseases, and we therefore propose that R‐Ras1 −/− and R‐Ras2 −/− neurological models are valuable approaches for the study of these myelin pathologies. Main Points: Hypomyelination caused by the absence of R‐Ras1/2 increases the energetic demands, partially solved by specific mitochondrial adaptations. Chronical energetic requirements trigger the accumulation of reactive oxygen species (ROS), which lead to axonal degeneration and functional loss.