Elovl4 5-bp deletion does not accelerate cone photoreceptor degeneration in an all-cone mouse

Schori, Christian; Agbaga, Martin-Paul; Brush, Richard S.; Ayyagari, Radha; Grimm, Christian; Samardzija, Marijana

doi:10.1371/journal.pone.0190514

Cited by 8 publications

(8 citation statements)

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“…These results on the surface would suggest that VLC-PUFA are not critical for photoreceptor structure. However, as reported by the Bernstein lab ( 135 , 136 ) and in our own studies in rodents ( 151 , 152 ), the levels of VLC-PUFA in the rod-dominant rodent retina are much higher than in cone-dominant retinas ( 151 ) and in the human macula ( 153 ). It is possible that differences in the amount of VLC-PUFA in the rodent retina relative to the human retina could account for the reason why mouse Elovl4 models without mutant ELOVL4 expression do not show significant defects in retinal function and structure.…”

Section: Roles Of Vlc-fa-containing Lipids In Retinal Functionsupporting

confidence: 65%

Very long chain fatty acid-containing lipids: a decade of novel insights from the study of ELOVL4

Yeboah

Lobanova

Brush

et al. 2021

Journal of Lipid Research

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Section: Roles Of Vlc-fa-containing Lipids In Retinal Functionsupporting

confidence: 65%

Very long chain fatty acid-containing lipids: a decade of novel insights from the study of ELOVL4

Yeboah

Lobanova

Brush

et al. 2021

Journal of Lipid Research

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“…Protein concentration was determined using a Bicinchonic Acid kit (Sigma-Aldrich, St. Louis, MO) after which 25 μg of total unboiled protein lysates were resolved on 4–20% polyacrylamide gels and transferred to nitrocellulose membrane. ELOVL4 was detected using previously characterized rabbit polyclonal ELOVL4 antibodies [ 1 ] that have been confirmed by other labs [ 38 , 39 ] to recognize ≈32-kDa ELOVL4 protein from mouse, rat, bovine, and porcine ELOVL4-expressing tissues and by specifically block binding by pre-incubation of the antibody with the antigenic peptide [ 1 ]. Immunolabeling of nitrocellulose membranes with this and other primary antibodies (Table 1 ) was performed at room temperature for 2 h in Intercept TBS Blocking Buffer (LI-COR).…”

Section: Methodsmentioning

confidence: 83%

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

et al. 2021

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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.

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“…Protein concentration was determined using Bicinchonic Acid kit (Sigma Aldrich, St. Louis, MO) after which 25 μg of total unboiled protein lysates were resolved on 4-20% polyacrylamide gels and transferred to nitrocellulose membrane. ELOVL4 was detected using previously characterized rabbit polyclonal ELOVL4 antibodies [1] that have been confirmed by other labs [38,39] to recognize ≈32-kDa ELOVL4 protein from mouse, rat, bovine, and porcine ELOVL4expressing tissues and by specifically block binding by pre-incubation of the antibody with the antigenic peptide [1]. Immunolabeling of nitrocellulose membranes with this and other primary antibodies (Table 1) was performed at room temperature for 2 hours in Intercept TBS Blocking Buffer (LI-COR).…”

Section: Western Blottingmentioning

confidence: 89%

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

Nagaraja

Sherry

Fessler

et al. 2021

Preprint

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Background: Spinocerebellar ataxias (SCA) are a group of neurodegenerative disorders characterized by neuronal degeneration leading to loss of motor coordination. 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 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. Methods: To understand role of ELOVL4 and its products in neuronal function and to evaluate the consequences of ELOVL4 mutations in pathogenesis of age-related SCA34, we generated a rat model of SCA34 by knock-in of the SCA34-causing 736T>G (p.W246G) ELOVL4 mutation. We performed biochemical, neuroanatomical and behavioral analyses by rotorod to measure motor function. We used electrophysiological recordings from cerebellar slices to determine the impact of the W246G mutation on neuronal function. Results were analyzed using GraphPad Prism Statistical software. Results: Heterozygous and homozygous rats carrying the W246G mutation developed impaired motor deficits by two 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 up 6 months of age showed normal cytoarchitectural organization despite the early-onset motor deficits and defects in synaptic plasticity. Conclusions: Our results point to ELOVL4 and its products being essential for motor function and cerebellar synaptic plasticity. The results further suggest that in SCA34 patients, ataxia arises from primary impairment of synaptic plasticity and cerebellar network desynchronization that precedes cerebellar degeneration and loss of motor coordination with aging.

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Elovl4 5-bp deletion does not accelerate cone photoreceptor degeneration in an all-cone mouse

Cited by 8 publications

References 50 publications

Very long chain fatty acid-containing lipids: a decade of novel insights from the study of ELOVL4

Very long chain fatty acid-containing lipids: a decade of novel insights from the study of ELOVL4

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

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

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