W246G Mutant ELOVL4 Impairs Synaptic Plasticity in Parallel and Climbing Fibers and Causes Motor Defects in a Rat Model of SCA34.

Autor: Nagaraja RY; Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA.; Neuroscience Program, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA.; Cell Biology, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA., Sherry DM; Neuroscience Program, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA.; Cell Biology, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA.; Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA., Fessler JL; Cell Biology, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA., Stiles MA; Ophthalmology, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA.; Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA., Li F; Ophthalmology, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA.; Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA., Multani K; Ophthalmology, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA.; Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA., Orock A; Neuroscience Program, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA.; Reynolds Center on Aging, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA., Ahmad M; Neuroscience Program, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA.; Cell Biology, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA., Brush RS; Ophthalmology, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA.; Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA., Anderson RE; Neuroscience Program, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA.; Cell Biology, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA.; Ophthalmology, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA.; Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA., Agbaga MP; Neuroscience Program, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA. Martin-Paul-Agbaga@ouhsc.edu.; Cell Biology, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA. Martin-Paul-Agbaga@ouhsc.edu.; Ophthalmology, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA. Martin-Paul-Agbaga@ouhsc.edu.; Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA. Martin-Paul-Agbaga@ouhsc.edu.; Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA. Martin-Paul-Agbaga@ouhsc.edu., Deák F; Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA. FDeak@augusta.edu.; Neuroscience Program, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA. FDeak@augusta.edu.; Reynolds Center on Aging, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK, 73104, USA. FDeak@augusta.edu.; Dept. of Neuroscience & Regenerative Medicine, Medical College of Georgia, 1120 15th Str, CA4010, Augusta, GA, 30912, USA. FDeak@augusta.edu.
Jazyk: angličtina
Zdroj: Molecular neurobiology [Mol Neurobiol] 2021 Oct; Vol. 58 (10), pp. 4921-4943. Date of Electronic Publication: 2021 Jul 05.
DOI: 10.1007/s12035-021-02439-1
Abstrakt: Spinocerebellar ataxia (SCA) is a neurodegenerative disorder characterized by ataxia and cerebellar atrophy. 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 caused by mutations in ELOVL4 (ELOngation of Very Long-chain fatty acids 4), a fatty acid elongase essential for biosynthesis of Very Long Chain Saturated and Polyunsaturated Fatty Acids (VLC-SFA and VLC-PUFA, resp., ≥28 carbons), which have important functions in the brain, skin, retina, Meibomian glands, testes, and sperm. We generated a rat model of SCA34 by knock-in of the SCA34-causing 736T>G (p.W246G) ELOVL4 mutation. Rats carrying the mutation developed impaired motor deficits by 2 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 showed normal cytoarchitectural organization with no evidence of degeneration out to 6 months of age. These results point to ELOVL4 as essential for motor function and cerebellar synaptic plasticity. The results further suggest that ataxia in SCA34 patients may arise from a primary impairment of synaptic plasticity and cerebellar network desynchronization before onset of neurodegeneration and progression of the disease at a later age.
(© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)
Databáze: MEDLINE
Externí odkaz: