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

Abstract

Spinocerebellar ataxias (SCA) are a group of neurodegenerative disorders caused by a number of different mutations the leads to loss of motor coordination 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. To understand the consequences of ELOVL4 mutations in pathogenesis of SCA34, we generated a rat model of SCA34 by knock-in of the SCA34-causing 736T>G (p.W246G) ELOVL4 mutation. We show that heterozygous and homozygous rats carrying the W246G mutation developed impaired motor deficits by two months of age. Our electrophysiological studies using cerebellar slices found marked reduction of long-term potentiation at parallel fiber synapses and long-term depression at climbing fiber synapses onto Purkinje cells in the homozygous W246G mutant rats. Our results further point to ELOVL4 products as being essential for motor function and cerebellar synaptic plasticity. These results suggest that in SCA34 patients, ataxia likely arises from primary impairment of synaptic plasticity and cerebellar network desynchronization that precedes cerebellar degeneration and loss of motor coordination with aging.