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

Raghavendra Y Nagaraja,Mohiuddin Ahmad,Feng Li,David M Sherry,Karanpreet Multani,Robert E Anderson,Richard S Brush,Megan A Stiles,Ferenc Deák,Jennifer L Fessler,Albert Orock,Martin-Paul Agbaga

doi:10.1007/s12035-021-02439-1

Abstract

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.

Highlights

Lipids are fundamental biological molecules that play many important roles in the central nervous system
Heterozygous inheritance of the W246G ELOngation of Very Long chain fatty acids-4 (ELOVL4) mutation results in motor deficits, mimicking the autosomal dominant inheritance pattern of human spinocerebellar ataxia-34 (SCA34). These studies demonstrate that homozygous inheritance of SCA34-causing mutations in ELOVL4 leads to motor impairment similar to that in heterozygotes, rather than the much more severe neuro-ichthyosis that arises from homozygous inheritance of autosomal dominant Stargardt-like macular dystrophy (STGD3)-causing mutations in exon 6 [3] or recessive ELOVL4 mutations that cause early truncation of the protein [18, 19]
These findings suggest that selective decrease of very long chain saturated fatty acids (VLC-SFA) synthesis by the W246G ELOVL4 mutation may contribute to SCA34

Summary

Introduction

Lipids are fundamental biological molecules that play many important roles in the central nervous system. ELOVL4 and its VLC-SFA and VLC-PUFA products are of critical importance to the CNS [7]. Heterozygous inheritance of several different ELOVL4 mutations in exon 6 that cause early truncation of the ELOVL4 protein and loss of the ER-retention signal in the C-terminus leads to autosomal dominant Stargardt-like macular dystrophy (STGD3), an aggressive juvenile-onset macular degeneration [8,9,10,11]. Patients with STGD3 show no CNS or skin phenotypes. Heterozygous inheritance of several different point mutations in ELOVL4 causes autosomal dominant spinocerebellar ataxia-34 (SCA34) with or without erythrokeratodermia variabilis (EKV, a skin condition) [12,13,14,15,16,17]. No human patients with homozygous inheritance of STGD3 or SCA34 alleles have been reported

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