{"doi":"10.4103/nrr.nrr-d-24-00436","title":"Emerging insights into the function of very long chain fatty acids at cerebellar synapses","abstract":"Very long chain-saturated and -polyunsaturated fatty acids (VLC-SFA and VLC-PUFA, respectively) are a functionally important class of fatty acids containing 28 carbons or more in their acyl chain. They are synthesized by the elongation of very long fatty acids-4 (ELOVL4) enzyme, expressed mainly in the brain, retina, skin, testes, and meibomian gland, where these fatty acids are found (Agbaga et al., 2008). Further, these organs exhibit tissue-specific VLC-PUFA and VLC-SFA biosynthesis and incorporation into complex lipids for specific functions. In the brain, skin, and Meibomian glands, the ELOVL4 mainly makes VLC-SFA, which are incorporated into complex sphingolipids. In the retina, the ELOVL4 makes VLC-PUFA that are incorporated into phosphatidylcholine, that are critical for visual function, while in testes and sperm, the VLC-PUFA are incorporated into sphingolipids that are critical for fertility (Yeboah et al., 2021). Elongation of very long fatty acids-4 variants cause neurological disorders: Though VLC-SFA in the brain were reported over three decades ago to be associated with Zellweger spectrum disorders (Moser, 1987), little is known about their importance in neuronal function. The significance of VLC-SFA in brain function became clearer with the discovery that several mutations in the ELOVL4 gene cause distinct neurological diseases that vary according to the mutation and its inheritance pattern (Yeboah et al., 2021). Recessive ELOVL4 mutations that result in an inactive enzyme lead to neuroichthyosis, which manifests as severe seizures, intellectual disability, spasticity, ichthyosis, and early death (Aldahmesh et al., 2011). Heterozygous inheritance of any of several different ELOVL4 point mutations causes autosomal dominant spinocerebellar ataxia-34 (SCA34), a late-onset neurodegenerative disease of the cerebellum. This condition is characterized by cerebellar dysfunction manifested as gait ataxia, limb ataxia, dysarthria, and eye movement abnormalities (Ozaki et al., 2015; Yeboah et al., 2021). Some patients also show pyramidal tract signs, cognitive impairment, and erythrokeratodermia variabilis, a disorder of the skin. Magnetic resonance imaging of SCA34 patients shows age-related progressive cerebellar and pontine atrophy. These findings suggest that the cerebellum is particularly vulnerable to the disrupted function of ELOVL4 in the production of VLC-SFA. In recent years, the number of patients diagnosed with SCA34 has steadily increased due to the growing use of genetic testing. The most common SCA34-causing ELOVL4 variants that have been reported are L168F, L168S, Q180P, T233M, I171T, and W246G (Yeboah et al., 2021). All of these mutations occur downstream of the enzyme’s catalytic site and are predicted to impair VLC-SFA biosynthesis to varying degrees, leading to different ages of onset. For instance, a recent report identified a patient with the SCA34-causing L168S variant who developed cerebellar ataxia and died within the first decade of life (Gyening et al., 2023a), whereas patients with the L168F variant do not develop ataxia until their fourth or fifth decade of life. As genetic testing becomes more accessible, it is likely that additional ELOVL4 variants associated with SCA34 will be identified, giving us a clearer understanding of the prevalence of different variants causing the disease. Elongation of very long fatty acids-4 expression in the cerebellum: ELOVL4 is expressed in most neuronal cell types in the cerebellum, with particularly strong expression in cerebellar granule cells (Sherry et al., 2017). The neurons in the molecular layer, presumably the molecular layer interneurons, showed strong labeling, whereas the Purkinje cells showed moderate but clear staining for ELOVL4. This pattern of staining was consistent across different lobules of the cerebellar cortex. Many neurons in the deep cerebellar nuclei also showed intense labeling for ELOVL4. VLC-SFA-containing lipids are likely to foll","journal":"Neural Regeneration Research","year":2024,"id":480977,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9468,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":728556,"name":"Mohiuddin Ahmad","orcid":"0000-0002-0976-9620","position":1,"is_corresponding":false},{"id":351327,"name":"Martin‐Paul Agbaga","orcid":"0000-0002-1920-915X","position":0,"is_corresponding":true}],"reference_count":12,"raw_metadata":null,"created_at":"2026-07-19T02:07:06.225103Z","pmid":"39104105","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}