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

• DOI: 10.1007/s12035-021-02439-1
• Publication Date: 2021-07-05T17:03:31Z
• Authors: Raghavendra Y. Na...; David M. Sherry; Jennifer L. Fessler; Megan A. Stiles; Feng Li; Karanpreet Multani; Albert Orock; Mohiuddin Ahmad; Richard S. Brush; Robert E. Anderson; Martin-Paul Agbaga; Ferenc Deák
• Keywords: Parallel fiber; Climbing fiber; Mossy fiber (hippocampus)

Spinocerebellar ataxia (SCA) is a neurodegenerative disorder characterized by and cerebellar atrophy. A number of different mutations gives rise to types SCA with characteristic ages onset, symptomatology, rates progression. type 34 (SCA34) caused in ELOVL4 (ELOngation Very Long-chain fatty acids 4), acid elongase essential for biosynthesis Long Chain Saturated Polyunsaturated Fatty Acids (VLC-SFA VLC-PUFA, resp., ≥28 carbons), which have important functions the brain, skin, retina, Meibomian glands, testes, sperm. We generated rat model SCA34 knock-in SCA34-causing 736T>G (p.W246G) mutation. Rats carrying mutation developed impaired motor deficits 2 months age. To understand mechanism these deficits, we performed electrophysiological studies using slices from rats homozygous W246G mutant found marked reduction long-term potentiation at parallel fiber synapses depression climbing onto Purkinje cells. Neuroanatomical analysis cerebellum showed normal cytoarchitectural organization no evidence degeneration out 6 These results point as function synaptic plasticity. The further suggest that patients may arise primary impairment plasticity network desynchronization before onset neurodegeneration progression disease later