The Elovl4 Spinocerebellar Ataxia-34 Mutation 736T>G (p.W246G) Impairs Retinal Function in the Absence of Photorecept
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The Elovl4 Spinocerebellar Ataxia-34 Mutation 736T>G (p.W246G) Impairs Retinal Function in the Absence of Photoreceptor Degeneration Martin-Paul Agbaga 1,2,3,4,5 & Megan A. Stiles 1,2 & Richard S. Brush 1,2 & Michael T. Sullivan 1,2 & Adeline Machalinski 1,2 & Kenneth L. Jones 3,5 & Robert E. Anderson 1,2,3,4 & David M. Sherry 3,4,6 Received: 16 April 2020 / Accepted: 30 July 2020 # The Author(s) 2020
Abstract Elongation of very long chain fatty acids-4 (ELOVL4) is essential for synthesis of very long chain polyunsaturated and saturated fatty acids (VLC-PUFA and VLC-SFA, respectively) of chain length greater than 26 carbons. Mutations in the ELOVL4 gene cause several distinct neurodegenerative diseases including Stargardt-like macular dystrophy (STGD3), spinocerebellar ataxia 34 (SCA34), and a neuro-ichthyotic syndrome with severe seizures and spasticity, as well as erythrokeratitis variabilis (EKV), a skin disorder. However, the relationship between ELOVL4 mutations, its VLC-PUFA and VLC-SFA products, and specific neurological symptoms remains unclear. We generated a knock-in rat line (SCA34-KI) that expresses the 736T>G (p.W246G) form of ELOVL4 that causes human SCA34. Lipids were analyzed by gas chromatography and mass spectrometry. Retinal function was assessed using electroretinography. Retinal integrity was assessed by histology, optical coherence tomography, and immunolabeling. Analysis of retina and skin lipids showed that the W246G mutation selectively impaired synthesis of VLCSFA, but not VLC-PUFA. Homozygous SCA34-KI rats showed reduced ERG a- and b-wave amplitudes by 90 days of age, particularly for scotopic responses. Anatomical analyses revealed no indication of neurodegeneration in heterozygote or homozygote SCA34-KI rats out to 6–7 months of age. These studies reveal a previously unrecognized role for VLC-SFA in regulating retinal function, particularly transmission from photoreceptors to the inner retina, in the absence of neurodegeneration. Furthermore, these findings suggest that the tissue specificity and symptoms associated with disease-causing ELOVL4 mutations likely arise from selective differences in the ability of the mutant ELOVL4 enzymes to support synthesis of VLC-PUFA and/or VLC-SFA. Keywords Very long chain fatty acids . Neurodegeneration . Stargardt-like macular dystrophy . Retina . Cerebellum
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-020-02052-8) contains supplementary material, which is available to authorized users. * Martin-Paul Agbaga [email protected] * David M. Sherry [email protected] 1
2
Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA Department of Ophthalmology, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, DMEI 428PP, Oklahoma City, OK 73104, USA
3
Department of Cell Biology, University of Oklahoma Health Sciences Center, 940 SL Young Blvd, BMSB-536, Oklahoma City, OK 73104, USA
4
Oklahoma Center for Neuroscienc
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