W246G Mutant ELOVL4 Impairs Synaptic Plasticity in Parallel and Climbing Fibers and Causes Motor Defects in a Rat Model of SCA34
Year: 2021
Type: article
Abstract: Background: Spinocerebellar ataxias (SCA) are a group of neurodegenerative disorders characterized by neuronal degeneration leading to loss of motor coordination. A number of different mutations gives rise to different types of SCA with characteristic ages of onset, symptomatology, and rates of progression. SCA type 34 (SCA34) is an age-related cerebellar neurodegenerative disorder caused by mutations in the fatty acid elongase-4 (ELOVL4). The ELOVL4 is an essential enzyme that mediates biosynthesis of Very Long Chain Saturated and Polyunsaturated Fatty Acids (VLC-SFA and VLC-PUFA, resp., ≥28 carbons) that are critical for the normal function of brain, skin, retina, Meibomian glands, and testes in which ELOVL4 is expressed. Global deletion or homozygous expression of truncated mutant ELOVL4 that lack VLC-SFA and VLC-PUFA biosynthesis cause severe skin disorders, seizures and neonatal mortality in rodents and humans. Methods: To understand role of ELOVL4 and its products in neuronal function and to evaluate the consequences of ELOVL4 mutations in pathogenesis of age-related SCA34, we generated a rat model of SCA34 by knock-in of the SCA34-causing 736T>G (p.W246G) ELOVL4 mutation. We performed biochemical, neuroanatomical and behavioral analyses by rotorod to measure motor function. We used electrophysiological recordings from cerebellar slices to determine the impact of the W246G mutation on neuronal function. Results were analyzed using GraphPad Prism Statistical software. Results: Heterozygous and homozygous rats carrying the W246G mutation developed impaired motor deficits by two months of age. To understand the mechanism of these motor deficits, we performed electrophysiological studies using cerebellar slices from rats homozygous for W246G mutant ELOVL4 and found marked reduction of long-term potentiation at parallel fiber synapses and long-term depression at climbing fiber synapses onto Purkinje cells. Neuroanatomical analysis of the cerebellum up 6 months of age showed normal cytoarchitectural organization despite the early-onset motor deficits and defects in synaptic plasticity. Conclusions: Our results point to ELOVL4 and its products being essential for motor function and cerebellar synaptic plasticity. The results further suggest that in SCA34 patients, ataxia arises from primary impairment of synaptic plasticity and cerebellar network desynchronization that precedes cerebellar degeneration and loss of motor coordination with aging.
Source: Molecular Neurobiology
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,860
Funders: Presbyterian Health Foundation, Research to Prevent Blindness, Oklahoma Center for the Advancement of Science and Technology, National Institutes of Health, Directorate for Biological Sciences, University of California, Davis, National Institute on Aging, National Eye Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Research Resources
Awards: Core Grant for Vision Research, Defining the Mechanism of Altered Very Long Chain Fatty Acid Metabolism in Neuro-Ichthyotic Disorders., G2734434967, G2966035099, UC Davis/NIH NeuroMab Facility, Novel role of very long chain fatty acids in the brain, G5305259855, G5466471765, Role of VAMP1 in synaptic transmission and Alzheimer's dementia, Essential Role of Very Long Chain Fatty Acids in Retinal Function, Lipid Metabolism in the Retina, Zebrafish International Resource Center, Genetics and Biology of Malignant Glioma, G9000171446, P30 Center Core Grant for Vision Research, Cellular and Molecular Geroscience CoBRE: Phase 2
OpenAlex ID: W3132094379