Distribution of ELOVL4 in the Developing and Adult Mouse Brain

Abstract

ELOngation of Very Long chain fatty acids (ELOVL)-4 is essential for the synthesis of very long chain-fatty acids (fatty acids with chain lengths ≥ 28 carbons). The functions of ELOVL4 and its very long-chain fatty acid products are poorly understood at present. However, mutations in ELOVL4 cause neurodevelopmental or neurodegenerative diseases that vary according to the mutation and inheritance pattern. Heterozygous inheritance of different ELOVL4 mutations causes Stargardt-like Macular Dystrophy or Spinocerebellar Ataxia type 34. Homozygous inheritance of ELOVL4 mutations causes more severe disease characterized by seizures, intellectual disability, ichthyosis, and premature death. To better understand ELOVL4 and very long chain fatty acid function in the brain, we examined ELOVL4 expression in the mouse brain between embryonic day 18 and postnatal day 60 by immunolabeling using ELOVL4 and other marker antibodies. ELOVL4 was widely expressed in a region-and cell type-specific manner, and was restricted to cell bodies, consistent with its known localization to endoplasmic reticulum. ELOVL4 labeling was most prominent in gray matter, although labeling also was present in some cells located in white matter. ELOVL4 was widely expressed in the developing brain by embryonic day 18 and was especially pronounced in regions underlying the lateral ventricles and other neurogenic regions. The basal ganglia in particular showed intense ELOVL4 labeling at this stage. In the postnatal brain, cerebral cortex, hippocampus, cerebellum, thalamus, hypothalamus, midbrain, pons, and medulla all showed prominent ELOVL4 labeling, although ELOVL4 distribution was not uniform across all cells or subnuclei within these regions. In contrast, the basal ganglia showed little ELOVL4 labeling in the postnatal brain. Double labeling studies showed that ELOVL4 was primarily expressed by neurons, although presumptive oligodendrocytes located in white matter tracts also showed labeling. Little or no ELOVL4 labeling was present in astrocytes or radial glial cells. These findings suggest that ELOVL4 and its Sherry et al. ELOVL4 Distribution in the Brain very long chain fatty acid products are important in many parts of the brain and that they are particularly associated with neuronal function. Specific roles for ELOVL4 and its products in oligodendrocytes and myelin and in cellular proliferation, especially during development, are possible.

Characterization of the phenotype with cognitive impairment and protein mislocalization in SCA34

“…3,4 ELOVL4 is involved in the elongation of VLCFA with carbon chains of 24 atoms or longer and catalyzes the rate-limiting reaction in the production of 2 distinct products: very-long-chain saturated fatty acids (VLC-SFAs), which are involved in skin barrier formation and sphingolipid production, and VLC polyunsaturated fatty acids, which are essential for photoreceptor cells of the macula and also for production of sphingolipids. 24 In the cerebellum, the protein is located in all parts of the cerebellar cortex and deep cerebellar nuclei, and it is mainly expressed in neurons and oligodendrocytes, 25 which is compatible with the role of VLC-SFA in myelin production. Skin appears as a relevant tissue to investigate the biochemical anomalies associated with ELOVL4 mutations, considering that the brain and skin are the 2 human organs with the highest concentrations of sphingolipids, some of which are dependent on the presence of ELOVL4 for synthesis.…”

The Elovl4 Spinocerebellar Ataxia-34 Mutation 736T>G (p.W246G) Impairs Retinal Function in the Absence of Photoreceptor Degeneration

“…Immunolabeling was performed as described previously [ 3 , 43 ]. Frozen sections of fixed eyecups were rehydrated in Hank’s buffered salt solution (HBSS, pH 7.2), and non-specific labeling was blocked using a solution containing 2–10% normal goat serum plus 5% bovine serum albumin, 1% fish gelatin, and 0.1–0.5% Triton X-100 in HBSS (“blocker”).…”

ELOVL4: Very long-chain fatty acids serve an eclectic role in mammalian health and function

“…In the hippocampus, a known locus for temporal medial lobe seizures (Navidhamidi et al, 2017; Soussi et al, 2015), ELOVL4 expression was very strong in CA3 and the polymorphic layer of the dentate gyrus (DG), as well as in the subiculum and entorhinal cortex, which provide synaptic input to the hippocampal circuit. The neurons to which DG projects in CA2 and CA1 regions showed weaker ELOVL4 labeling (Hopiavuori et al, 2017b; Sherry et al, 2017) (Fig. 8B).…”

“…In P20 mice, ELOVL4 is expressed in several different brain regions, with highest expression found within neurons of the cerebellum, thalamus, hippocampus, and cortex (Hopiavuori et al, 2017b; Sherry et al, 2017) (Fig. 8A).…”