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Spinocerebellar ataxia 38: structure–function analysis shows ELOVL5 G230V is proteotoxic, conformationally altered and a mutational hotspot

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Ferrero, Enza, Di Gregorio, Eleonora, Ferrero, Marta, Ortolan, Erika, Moon, Young-Ah, Di Campli, Antonella, Pavinato, Lisa, Mancini, Cecilia, Tripathy, Debasmita, Manes, Marta, Hoxha, Eriola, Costanzi, Chiara, Pozzi, Elisa, Rossi Sebastiano, Matteo, Mitro, Nico, Tempia, Filippo, Caruso, Donatella, Borroni, Barbara, Basso, Manuela, Sallese, Michele, Brusco, Alfredo·2023·Human Genetics
DOI 10.1007/s00439-023-02572-yPMC PMC10449689

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Abstract

Fatty acid elongase ELOVL5 is part of a protein family of multipass transmembrane proteins that reside in the endoplasmic reticulum where they regulate long-chain fatty acid elongation. A missense variant (c.689G>T p.Gly230Val) in ELOVL5 causes Spinocerebellar Ataxia subtype 38 (SCA38), a neurodegenerative disorder characterized by autosomal dominant inheritance, cerebellar Purkinje cell demise and adult-onset ataxia. Having previously showed aberrant accumulation of p.G230V in the Golgi complex, here we further investigated the pathogenic mechanisms triggered by p.G230V, integrating functional studies with bioinformatic analyses of protein sequence and structure. Biochemical analysis showed that p.G230V enzymatic activity was normal. In contrast, SCA38-derived fibroblasts showed reduced expression of ELOVL5, Golgi complex enlargement and increased proteasomal degradation with respect to controls. By heterologous overexpression, p.G230V was significantly more active than wild-type ELOVL5 in triggering the unfolded protein response and in decreasing viability in mouse cortical neurons. By homology modelling, we generated native and p.G230V protein structures whose superposition revealed a shift in Loop 6 in p.G230V that altered a highly conserved intramolecular disulphide bond. The conformation of this bond, connecting Loop 2 and Loop 6, appears to be elongase-specific. Alteration of this intramolecular interaction was also observed when comparing wild-type ELOVL4 and the p.W246G variant which causes SCA34. We demonstrate by sequence and structure analyses that ELOVL5 p.G230V and ELOVL4 p.W246G are position-equivalent missense variants. We conclude that SCA38 is a conformational disease and propose combined loss of function by mislocalization and gain of toxic function by ER/Golgi stress as early events in SCA38 pathogenesis.

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  1. Agbaga MP, Stiles MA, Brush RS, Sullivan MT, Machalinski A, Jones KL, Anderson RE, Sherry DM (2020) The Elovl4 spinocerebellar ataxia-34 mutation 736T>G (p. W246G) impairs retinal function in the absence of photoreceptor degeneration. Mol Neurobiol 57:4735–4753. https://doi.org/10.1007/s12035-020-02052-8 · DOI
  2. Ashizawa T, Oz G, Paulson HL (2018) Spinocerebellar ataxias: prospects and challenges for therapy development. Nat Rev Neurol 14:590–605. https://doi.org/10.1038/s41582-018-0051-6 · DOI
  3. Atkinson R, Leung J, Bender J, Kirkcaldie M, Vickers J, King A (2021) TDP-43 mislocalization drives neurofilament changes in a novel model of TDP-43 proteinopathy. Dis Model Mech. https://doi.org/10.1242/dmm.047548 · DOI
  4. Balchin D, Hayer-Hartl M, Hartl FU (2016) In vivo aspects of protein folding and quality control. Science 353:aac4354. https://doi.org/10.1126/science.aac4354 · DOI
  5. Barnes MR, Gray IC (2003) Bioinformatics for geneticists. Wiley, New York · DOI
  6. Basso M, Berlin J, Xia L, Sleiman SF, Ko B, Haskew-Layton R, Kim E, Antonyak MA, Cerione RA, Iismaa SE, Willis D, Cho S, Ratan RR (2012) Transglutaminase inhibition protects against oxidative stress-induced neuronal death downstream of pathological ERK activation. J Neurosci 32:6561–6569. https://doi.org/10.1523/JNEUROSCI.3353-11.2012 · DOI
  7. Bazinet RP, Laye S (2014) Polyunsaturated fatty acids and their metabolites in brain function and disease. Nat Rev Neurosci 15:771–785. https://doi.org/10.1038/nrn3820 · DOI
  8. Bechtel TJ, Weerapana E (2017) From structure to redox: the diverse functional roles of disulfides and implications in disease. Proteomics. https://doi.org/10.1002/pmic.201600391 · DOI
  9. Bernstein PS, Tammur J, Singh N, Hutchinson A, Dixon M, Pappas CM, Zabriskie NA, Zhang K, Petrukhin K, Leppert M, Allikmets R (2001) Diverse macular dystrophy phenotype caused by a novel complex mutation in the ELOVL4 gene. Investig Ophthalmol vis Sci 42:3331–3336
  10. Boot A, Oosting J, van Eendenburg JDH, Kuppen PJK, Morreau H, van Wezel T (2017) Methylation associated transcriptional repression of ELOVL5 in novel colorectal cancer cell lines. PLoS ONE 12:e0184900. https://doi.org/10.1371/journal.pone.0184900 · DOI
  11. Borroni B, Di Gregorio E, Orsi L, Vaula G, Costanzi C, Tempia F, Mitro N, Caruso D, Manes M, Pinessi L, Padovani A, Brusco A, Boccone L (2016) Clinical and neuroradiological features of spinocerebellar ataxia 38 (SCA38). Parkinsonism Relat Disord 28:80–86. https://doi.org/10.1016/j.parkreldis.2016.04.030 · DOI
  12. Brenna JT, Kothapalli KSD (2021) New understandings of the pathway of long-chain polyunsaturated fatty acid biosynthesis. Curr Opin Clin Nutr Metab Care. https://doi.org/10.1097/MCO.0000000000000810 · DOI
  13. Briant K, Johnson N, Swanton E (2017) Transmembrane domain quality control systems operate at the endoplasmic reticulum and Golgi apparatus. PLoS ONE 12:e0173924. https://doi.org/10.1371/journal.pone.0173924 · DOI
  14. Brusco A, Di Gregorio E, Borroni B (2019) Spinocerebellar ataxia type 38. In: Adam MP, Mirzaa GM, Pagon RA et al (eds) GeneReviews® [Internet]. University of Washington, Seattle. Available from: https://www.ncbi.nlm.nih.gov/books/NBK543515/
  15. Bushart DD, Murphy GG, Shakkottai VG (2016) Precision medicine in spinocerebellar ataxias: treatment based on common mechanisms of disease. Ann Transl Med 4:25. https://doi.org/10.3978/j.issn.2305-5839.2016.01.06 · DOI
  16. Cadieux-Dion M, Turcotte-Gauthier M, Noreau A, Martin C, Meloche C, Gravel M, Drouin CA, Rouleau GA, Nguyen DK, Cossette P (2014) Expanding the clinical phenotype associated with ELOVL4 mutation: study of a large French–Canadian family with autosomal dominant spinocerebellar ataxia and erythrokeratodermia. JAMA Neurol 71:470–475. https://doi.org/10.1001/jamaneurol.2013.6337 · DOI · Paper page
  17. Capriotti E, Fariselli P, Casadio R (2005) I-Mutant2.0: predicting stability changes upon mutation from the protein sequence or structure. Nucleic Acids Res 33:W306–W310. https://doi.org/10.1093/nar/gki375 · DOI
  18. Capriotti E, Fariselli P, Rossi I, Casadio R (2008) A three-state prediction of single point mutations on protein stability changes. BMC Bioinform 9(Suppl 2):S6. https://doi.org/10.1186/1471-2105-9-S2-S6 · DOI
  19. Centenera MM, Scott JS, Machiels J, Nassar ZD, Miller DC, Zininos I, Dehairs J, Burvenich IJG, Zadra G, Chetta P, Bango C, Evergren E, Ryan NK, Gillis JL, Mah CY, Tieu T, Hanson AR, Carelli R, Bloch K, Panagopoulos V, Waelkens E, Derua R, Williams ED, Evdokioou A, Cifuentes-Rius A, Voelcker NH, Mills IG, Tilley WD, Scott AM, Loda M, Selth LA, Swinnen JV, Butler LM (2021) ELOVL5 is a critical and targetable fatty acid elongase in prostate cancer. Cancer Res. https://doi.org/10.1158/0008-5472.CAN-20-2511 · DOI
  20. Ciechanover A, Kwon YT (2015) Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies. Exp Mol Med 47:e147. https://doi.org/10.1038/emm.2014.117 · DOI · Paper page
  21. Conn PM, Ulloa-Aguirre A (2011) Pharmacological chaperones for misfolded gonadotropin-releasing hormone receptors. Adv Pharmacol 62:109–141. https://doi.org/10.1016/B978-0-12-385952-5.00008-7 · DOI
  22. Cosson P, Perrin J, Bonifacino JS (2013) Anchors aweigh: protein localization and transport mediated by transmembrane domains. Trends Cell Biol 23:511–517. https://doi.org/10.1016/j.tcb.2013.05.005 · DOI
  23. Creedican S, Talty A, Fitzgerald SP, Samali A, Richardson C, Gorman AM, Martin K (2019) Application of a new multiplexed array for rapid, sensitive, simultaneous and quantitative assessment of spliced and unspliced XBP1. Biol Proced Online 21:22. https://doi.org/10.1186/s12575-019-0111-3 · DOI
  24. Deak F, Anderson RE, Fessler JL, Sherry DM (2019) Novel cellular functions of very long chain-fatty acids: insight from ELOVL4 mutations. Front Cell Neurosci 13:428. https://doi.org/10.3389/fncel.2019.00428 · DOI
  25. Denic V, Weissman JS (2007) A molecular caliper mechanism for determining very long-chain fatty acid length. Cell 130:663–677. https://doi.org/10.1016/j.cell.2007.06.031 · DOI
  26. DePristo MA, Weinreich DM, Hartl DL (2005) Missense meanderings in sequence space: a biophysical view of protein evolution. Nat Rev Genet 6:678–687. https://doi.org/10.1038/nrg1672 · DOI
  27. Di Gregorio E, Borroni B, Giorgio E, Lacerenza D, Ferrero M, Lo Buono N, Ragusa N, Mancini C, Gaussen M, Calcia A, Mitro N, Hoxha E, Mura I, Coviello DA, Moon YA, Tesson C, Vaula G, Couarch P, Orsi L, Duregon E, Papotti MG, Deleuze JF, Imbert J, Costanzi C, Padovani A, Giunti P, Maillet-Vioud M, Durr A, Brice A, Tempia F, Funaro A, Boccone L, Caruso D, Stevanin G, Brusco A (2014) ELOVL5 mutations cause spinocerebellar ataxia 38. Am J Hum Genet 95:209–217. https://doi.org/10.1016/j.ajhg.2014.07.001 · DOI
  28. Dombkowski AA, Sultana KZ, Craig DB (2014) Protein disulfide engineering. FEBS Lett 588:206–212. https://doi.org/10.1016/j.febslet.2013.11.024 · DOI
  29. Gasteiger E, Gattiker A, Hoogland C, Ivanyi I, Appel RD, Bairoch A (2003) ExPASy: the proteomics server for in-depth protein knowledge and analysis. Nucleic Acids Res 31:3784–3788. https://doi.org/10.1093/nar/gkg563 · DOI
  30. Gazulla J, Orduna-Hospital E, Benavente I, Rodriguez-Valle A, Osorio-Caicedo P, Alvarez-de Andres S, Garcia-Gonzalez E, Fraile-Rodrigo J, Fernandez-Tirado FJ, Berciano J (2020) Contributions to the study of spinocerebellar ataxia type 38 (SCA38). J Neurol 267:2288–2295. https://doi.org/10.1007/s00415-020-09840-1 · DOI
  31. Giroux JM, Barbeau A (1972) Erythrokeratodermia with ataxia. Arch Dermatol 106:183–188 · DOI
  32. Gyening YK, Chauhan NK, Tytanic M, Ea V, Brush RS, Agbaga MP (2023) ELOVL4 mutations that cause spinocerebellar ataxia-34 differentially alter very long chain fatty acid biosynthesis. J Lipid Res 64:100317. https://doi.org/10.1016/j.jlr.2022.100317 · DOI
  33. Hachem M, Belkouch M, Van Lo A, Picq M, Bernoud-Hubac N, Lagarde M (2020) Brain targeting with docosahexaenoic acid as a prospective therapy for neurodegenerative diseases and its passage across blood brain barrier. Biochimie 170:203–211. https://doi.org/10.1016/j.biochi.2020.01.013 · DOI
  34. Hartl FU (2017) Protein misfolding diseases. Annu Rev Biochem 86:21–26. https://doi.org/10.1146/annurev-biochem-061516-044518 · DOI
  35. Hayashi YY, Kono N, Arai H, Fujiwara Y, Ichi I (2020) Phosphorylation of Elovl5 changes its substrate preference to synthesize Mead acid in response to essential fatty acid deficiency. BioArchive. https://doi.org/10.1101/2020.01.31.929224 · DOI
  36. Hoxha E, Gabriele RMC, Balbo I, Ravera F, Masante L, Zambelli V, Albergo C, Mitro N, Caruso D, Di Gregorio E, Brusco A, Borroni B, Tempia F (2017) Motor deficits and cerebellar atrophy in Elovl5 knock out mice. Front Cell Neurosci 11:343. https://doi.org/10.3389/fncel.2017.00343 · DOI
  37. Huang M, Verbeek DS (2019) Why do so many genetic insults lead to Purkinje cell degeneration and spinocerebellar ataxia? Neurosci Lett 688:49–57. https://doi.org/10.1016/j.neulet.2018.02.004 · DOI
  38. Hwang JY, Lee HJ, Go MJ, Jang HB, Choi NH, Bae JB, Castillo-Fernandez JE, Bell JT, Spector TD, Lee HJ, Kim BJ (2018) Genome-wide methylation analysis identifies ELOVL5 as an epigenetic biomarker for the risk of type 2 diabetes mellitus. Sci Rep 8:14862. https://doi.org/10.1038/s41598-018-33238-9 · DOI
  39. Iqbal S, Perez-Palma E, Jespersen JB, May P, Hoksza D, Heyne HO, Ahmed SS, Rifat ZT, Rahman MS, Lage K, Palotie A, Cottrell JR, Wagner FF, Daly MJ, Campbell AJ, Lal D (2020) Comprehensive characterization of amino acid positions in protein structures reveals molecular effect of missense variants. Proc Natl Acad Sci USA 117:28201–28211. https://doi.org/10.1073/pnas.2002660117 · DOI
  40. Jacquemyn J, Cascalho A, Goodchild RE (2017) The ins and outs of endoplasmic reticulum-controlled lipid biosynthesis. EMBO Rep 18:1905–1921. https://doi.org/10.15252/embr.201643426 · DOI
  41. Jakobsson A, Westerberg R, Jacobsson A (2006) Fatty acid elongases in mammals: their regulation and roles in metabolism. Prog Lipid Res 45:237–249. https://doi.org/10.1016/j.plipres.2006.01.004 · DOI · Paper page
  42. Jump DB (2009) Mammalian fatty acid elongases. Methods Mol Biol 579:375–389. https://doi.org/10.1007/978-1-60761-322-0_19 · DOI · Paper page
  43. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alfoldi J, Wang Q, Collins RL, Laricchia KM, Ganna A, Birnbaum DP, Gauthier LD, Brand H, Solomonson M, Watts NA, Rhodes D, Singer-Berk M, England EM, Seaby EG, Kosmicki JA, Walters RK, Tashman K, Farjoun Y, Banks E, Poterba T, Wang A, Seed C, Whiffin N, Chong JX, Samocha KE, Pierce-Hoffman E, Zappala Z, O’Donnell-Luria AH, Minikel EV, Weisburd B, Lek M, Ware JS, Vittal C, Armean IM, Bergelson L, Cibulskis K, Connolly KM, Covarrubias M, Donnelly S, Ferriera S, Gabriel S, Gentry J, Gupta N, Jeandet T, Kaplan D, Llanwarne C, Munshi R, Novod S, Petrillo N, Roazen D, Ruano-Rubio V, Saltzman A, Schleicher M, Soto J, Tibbetts K, Tolonen C, Wade G, Talkowski ME, Genome Aggregation Database C, Neale BM, Daly MJ, MacArthur DG (2020) The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581:434–443. https://doi.org/10.1038/s41586-020-2308-7 · DOI · Paper page
  44. Katoh K, Rozewicki J, Yamada KD (2019) MAFFT online service: multiple sequence alignment, interactive sequence choice and visualization. Brief Bioinform 20:1160–1166. https://doi.org/10.1093/bib/bbx108 · DOI · Paper page
  45. Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJ (2015) The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc 10:845–858. https://doi.org/10.1038/nprot.2015.053 · DOI · Paper page
  46. Kerdiles OLS, Calon F (2017) Omega-3 polyunsaturated fatty acids and brain health: preclinical evidence for the prevention of neurodegenerative diseases. Trends Food Sci Technol 69:203–213. https://doi.org/10.1016/j.tifs.2017.09.003 · DOI
  47. Kihara A (2012) Very long-chain fatty acids: elongation, physiology and related disorders. J Biochem 152:387–395. https://doi.org/10.1093/jb/mvs105 · DOI
  48. Klockgether T, Mariotti C, Paulson HL (2019) Spinocerebellar ataxia. Nat Rev Dis Primers 5:24. https://doi.org/10.1038/s41572-019-0074-3 · DOI
  49. Kokubun H, Jin H, Aoe T (2019) Pathogenic effects of impaired retrieval between the endoplasmic reticulum and golgi complex. Int J Mol Sci. https://doi.org/10.3390/ijms20225614 · DOI
  50. Kopanos C, Tsiolkas V, Kouris A, Chapple CE, Albarca Aguilera M, Meyer R, Massouras A (2019) VarSome: the human genomic variant search engine. Bioinformatics 35:1978–1980. https://doi.org/10.1093/bioinformatics/bty897 · DOI
  51. Kovacs GG (2019) Molecular pathology of neurodegenerative diseases: principles and practice. J Clin Pathol 72:725–735. https://doi.org/10.1136/jclinpath-2019-205952 · DOI
  52. Laimer J, Hofer H, Fritz M, Wegenkittl S, Lackner P (2015) MAESTRO—multi agent stability prediction upon point mutations. BMC Bioinform 16:116. https://doi.org/10.1186/s12859-015-0548-6 · DOI
  53. Lal D, May P, Perez-Palma E, Samocha KE, Kosmicki JA, Robinson EB, Moller RS, Krause R, Nurnberg P, Weckhuysen S, De Jonghe P, Guerrini R, Niestroj LM, Du J, Marini C, Euro E-RESC, Ware JS, Kurki M, Gormley P, Tang S, Wu S, Biskup S, Poduri A, Neubauer BA, Koeleman BPC, Helbig KL, Weber YG, Helbig I, Majithia AR, Palotie A, Daly MJ (2020) Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders. Genome Med 12:28. https://doi.org/10.1186/s13073-020-00725-6 · DOI
  54. Lee JY, Nam M, Son HY, Hyun K, Jang SY, Kim JW, Kim MW, Jung Y, Jang E, Yoon SJ, Kim J, Kim J, Seo J, Min JK, Oh KJ, Han BS, Kim WK, Bae KH, Song J, Kim J, Huh YM, Hwang GS, Lee EW, Lee SC (2020) Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer. Proc Natl Acad Sci USA 117:32433–32442. https://doi.org/10.1073/pnas.2006828117 · DOI
  55. Li W, Sandhoff R, Kono M, Zerfas P, Hoffmann V, Ding BC, Proia RL, Deng CX (2007) Depletion of ceramides with very long chain fatty acids causes defective skin permeability barrier function, and neonatal lethality in ELOVL4 deficient mice. Int J Biol Sci 3:120–128. https://doi.org/10.7150/ijbs.3.120 · DOI
  56. Li G, Panday SK, Alexov E (2021) SAAFEC-SEQ: a sequence-based method for predicting the effect of single point mutations on protein thermodynamic stability. Int J Mol Sci. https://doi.org/10.3390/ijms22020606 · DOI
  57. Liu C, Mei M, Li Q, Roboti P, Pang Q, Ying Z, Gao F, Lowe M, Bao S (2017) Loss of the golgin GM130 causes Golgi disruption, Purkinje neuron loss, and ataxia in mice. Proc Natl Acad Sci USA 114:346–351. https://doi.org/10.1073/pnas.1608576114 · DOI
  58. Liu J, Huang Y, Li T, Jiang Z, Zeng L, Hu Z (2021) The role of the Golgi apparatus in disease (review). Int J Mol Med. https://doi.org/10.3892/ijmm.2021.4871 · DOI
  59. Logan S, Agbaga MP, Chan MD, Brush RS, Anderson RE (2014) Endoplasmic reticulum microenvironment and conserved histidines govern ELOVL4 fatty acid elongase activity. J Lipid Res 55:698–708. https://doi.org/10.1194/jlr.M045443 · DOI
  60. Lowe SL, Peter F, Subramaniam VN, Wong SH, Hong W (1997) A SNARE involved in protein transport through the Golgi apparatus. Nature 389:881–884. https://doi.org/10.1038/39923 · DOI
  61. Luck K, Kim DK, Lambourne L, Spirohn K, Begg BE, Bian W, Brignall R, Cafarelli T, Campos-Laborie FJ, Charloteaux B, Choi D, Cote AG, Daley M, Deimling S, Desbuleux A, Dricot A, Gebbia M, Hardy MF, Kishore N, Knapp JJ, Kovacs IA, Lemmens I, Mee MW, Mellor JC, Pollis C, Pons C, Richardson AD, Schlabach S, Teeking B, Yadav A, Babor M, Balcha D, Basha O, Bowman-Colin C, Chin SF, Choi SG, Colabella C, Coppin G, D’Amata C, De Ridder D, De Rouck S, Duran-Frigola M, Ennajdaoui H, Goebels F, Goehring L, Gopal A, Haddad G, Hatchi E, Helmy M, Jacob Y, Kassa Y, Landini S, Li R, van Lieshout N, MacWilliams A, Markey D, Paulson JN, Rangarajan S, Rasla J, Rayhan A, Rolland T, San-Miguel A, Shen Y, Sheykhkarimli D, Sheynkman GM, Simonovsky E, Tasan M, Tejeda A, Tropepe V, Twizere JC, Wang Y, Weatheritt RJ, Weile J, Xia Y, Yang X, Yeger-Lotem E, Zhong Q, Aloy P, Bader GD, De Las RJ, Gaudet S, Hao T, Rak J, Tavernier J, Hill DE, Vidal M, Roth FP, Calderwood MA (2020) A reference map of the human binary protein interactome. Nature 580:402–408. https://doi.org/10.1038/s41586-020-2188-x · DOI · Paper page
  62. Lukiw WJ, Bazan NG (2008) Docosahexaenoic acid and the aging brain. J Nutr 138:2510–2514. https://doi.org/10.3945/jn.108.096016 · DOI
  63. Machamer CE (2015) The Golgi complex in stress and death. Front Neurosci 9:421. https://doi.org/10.3389/fnins.2015.00421 · DOI
  64. Mallucci GR, Klenerman D, Rubinsztein DC (2020) Developing therapies for neurodegenerative disorders: insights from protein aggregation and cellular stress responses. Annu Rev Cell Dev Biol 36:165–189. https://doi.org/10.1146/annurev-cellbio-040320-120625 · DOI · Paper page
  65. Manes M, Alberici A, Di Gregorio E, Boccone L, Premi E, Mitro N, Pasolini MP, Pani C, Paghera B, Perani D, Orsi L, Costanzi C, Ferrero M, Zoppo A, Tempia F, Caruso D, Grassi M, Padovani A, Brusco A, Borroni B (2017) Docosahexaenoic acid is a beneficial replacement treatment for spinocerebellar ataxia 38. Ann Neurol 82:615–621. https://doi.org/10.1002/ana.25059 · DOI
  66. Manes M, Alberici A, Di Gregorio E, Boccone L, Premi E, Mitro N, Pasolini MP, Pani C, Paghera B, Orsi L, Costanzi C, Ferrero M, Tempia F, Caruso D, Padovani A, Brusco A, Borroni B (2019) Long-term efficacy of docosahexaenoic acid (DHA) for spinocerebellar ataxia 38 (SCA38) treatment: an open label extension study. Parkinsonism Relat Disord 63:191–194. https://doi.org/10.1016/j.parkreldis.2019.02.040 · DOI
  67. Matias Rodrigues JF, Wagner A (2009) Evolutionary plasticity and innovations in complex metabolic reaction networks. PLoS Comput Biol 5:e1000613. https://doi.org/10.1371/journal.pcbi.1000613 · DOI
  68. Matsusaki M, Kanemura S, Kinoshita M, Lee YH, Inaba K, Okumura M (2020) The protein disulfide isomerase family: from proteostasis to pathogenesis. Biochim Biophys Acta Gen Subj 1864:129338. https://doi.org/10.1016/j.bbagen.2019.04.003 · DOI
  69. Matus S, Valenzuela V, Medinas DB, Hetz C (2013) ER dysfunction and protein folding stress in ALS. Int J Cell Biol 2013:674751. https://doi.org/10.1155/2013/6747514 · DOI
  70. Maugeri A, Meire F, Hoyng CB, Vink C, Van Regemorter N, Karan G, Yang Z, Cremers FP, Zhang K (2004) A novel mutation in the ELOVL4 gene causes autosomal dominant Stargardt-like macular dystrophy. Investig Ophthalmol vis Sci 45:4263–4267. https://doi.org/10.1167/iovs.04-0078 · DOI
  71. Monroig O, Lopes-Marques M, Navarro JC, Hontoria F, Ruivo R, Santos MM, Venkatesh B, Tocher DR, Castro LF (2016) Evolutionary functional elaboration of the Elovl2/5 gene family in chordates. Sci Rep 6:20510. https://doi.org/10.1038/srep20510 · DOI
  72. Moon YA, Shah NA, Mohapatra S, Warrington JA, Horton JD (2001) Identification of a mammalian long chain fatty acyl elongase regulated by sterol regulatory element-binding proteins. J Biol Chem 276:45358–45366. https://doi.org/10.1074/jbc.M108413200 · DOI
  73. Moon YA, Hammer RE, Horton JD (2009) Deletion of ELOVL5 leads to fatty liver through activation of SREBP-1c in mice. J Lipid Res 50:412–423. https://doi.org/10.1194/jlr.M800383-JLR200 · DOI
  74. Moore KA, Hollien J (2012) The unfolded protein response in secretory cell function. Annu Rev Genet 46:165–183. https://doi.org/10.1146/annurev-genet-110711-155644 · DOI
  75. Nie L, Pascoa TC, Pike ACW, Bushell SR, Quigley A, Ruda GF, Chu A, Cole V, Speedman D, Moreira T, Shrestha L, Mukhopadhyay SMM, Burgess-Brown NA, Love JD, Brennan PE, Carpenter EP (2021) The structural basis of fatty acid elongation by the ELOVL elongases. Nat Struct Mol Biol 28:512–520. https://doi.org/10.1038/s41594-021-00605-6 · DOI
  76. Oka OB, Bulleid NJ (2013) Forming disulfides in the endoplasmic reticulum. Biochim Biophys Acta 1833:2425–2429. https://doi.org/10.1016/j.bbamcr.2013.02.007 · DOI
  77. Okuda A, Naganuma T, Ohno Y, Abe K, Yamagata M, Igarashi Y, Kihara A (2010) Hetero-oligomeric interactions of an ELOVL4 mutant protein: implications in the molecular mechanism of Stargardt-3 macular dystrophy. Mol vis 16:2438–2445
  78. Omasits U, Ahrens CH, Muller S, Wollscheid B (2014) Protter: interactive protein feature visualization and integration with experimental proteomic data. Bioinformatics 30:884–886. https://doi.org/10.1093/bioinformatics/btt607 · DOI
  79. Ori-McKenney KM, Jan LY, Jan YN (2012) Golgi outposts shape dendrite morphology by functioning as sites of acentrosomal microtubule nucleation in neurons. Neuron 76:921–930. https://doi.org/10.1016/j.neuron.2012.10.008 · DOI
  80. Ozaki K, Doi H, Mitsui J, Sato N, Iikuni Y, Majima T, Yamane K, Irioka T, Ishiura H, Doi K, Morishita S, Higashi M, Sekiguchi T, Koyama K, Ueda N, Miura Y, Miyatake S, Matsumoto N, Yokota T, Tanaka F, Tsuji S, Mizusawa H, Ishikawa K (2015) A novel mutation in ELOVL4 leading to spinocerebellar ataxia (SCA) with the hot cross bun sign but lacking erythrokeratodermia: a broadened spectrum of SCA34. JAMA Neurol 72:797–805. https://doi.org/10.1001/jamaneurol.2015.0610 · DOI · Paper page
  81. Patthy L (2008) Protein evolution, 2nd edn. Blackwell Publishing, Hoboken
  82. Peden AH, Ironside JW (2012) Molecular pathology in neurodegenerative diseases. Curr Drug Targets 13:1548–1559. https://doi.org/10.2174/138945012803530134 · DOI
  83. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF chimera—a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612. https://doi.org/10.1002/jcc.20084 · DOI
  84. Pfenninger KH (2009) Plasma membrane expansion: a neuron’s Herculean task. Nat Rev Neurosci 10:251–261. https://doi.org/10.1038/nrn2593 · DOI
  85. Praschberger R, Lowe SA, Malintan NT, Giachello CNG, Patel N, Houlden H, Kullmann DM, Baines RA, Usowicz MM, Krishnakumar SS, Hodge JJL, Rothman JE, Jepson JEC (2017) Mutations in membrin/GOSR2 reveal stringent secretory pathway demands of dendritic growth and synaptic integrity. Cell Rep 21:97–109. https://doi.org/10.1016/j.celrep.2017.09.004 · DOI
  86. Pulvirenti T, Giannotta M, Capestrano M, Capitani M, Pisanu A, Polishchuk RS, San Pietro E, Beznoussenko GV, Mironov AA, Turacchio G, Hsu VW, Sallese M, Luini A (2008) A traffic-activated Golgi-based signalling circuit coordinates the secretory pathway. Nat Cell Biol 10:912–922. https://doi.org/10.1038/ncb1751 · DOI
  87. Ricca I, Tessa A, Trovato R, Bacci GM, Santorelli FM (2020) Docosahexaenoic acid in ARSACS: observations in two patients. BMC Neurol 20:215. https://doi.org/10.1186/s12883-020-01803-3 · DOI
  88. Ruggiero C, Cancino J, Giannotta M, Sallese M (2014) Signaling initiated by the secretory compartment. Methods Enzymol 534:133–154. https://doi.org/10.1016/B978-0-12-397926-1.00008-1 · DOI
  89. Scheper W, Hoozemans JJ (2015) The unfolded protein response in neurodegenerative diseases: a neuropathological perspective. Acta Neuropathol 130:315–331. https://doi.org/10.1007/s00401-015-1462-8 · DOI
  90. Schmidt O, Weyer Y, Baumann V, Widerin MA, Eising S, Angelova M, Schleiffer A, Kremser L, Lindner H, Peter M, Frohlich F, Teis D (2019) Endosome and Golgi-associated degradation (EGAD) of membrane proteins regulates sphingolipid metabolism. EMBO J 38:e101433. https://doi.org/10.1525/embj.2018101433 · DOI
  91. Schneider CA, Rasband WS, Eliceiri KW (2012) NIH image to ImageJ: 25 years of image analysis. Nat Methods 9:671–675. https://doi.org/10.1038/nmeth.2089 · DOI · Paper page
  92. Schroder M, Kaufman RJ (2005) The mammalian unfolded protein response. Annu Rev Biochem 74:739–789. https://doi.org/10.1146/annurev.biochem.73.011303.074134 · DOI
  93. Shikama A, Shinozaki H, Takeuchi Y, Matsuzaka T, Aita Y, Murayama T, Sawada Y, Piao X, Toya N, Oya Y, Takarada A, Masuda Y, Nishi M, Kubota M, Izumida Y, Nakagawa Y, Iwasaki H, Kobayashi K, Yatoh S, Suzuki H, Yagyu H, Kawakami Y, Yamada N, Shimano H, Yahagi N (2015) Identification of human ELOVL5 enhancer regions controlled by SREBP. Biochem Biophys Res Commun 465:857–863. https://doi.org/10.1016/j.bbrc.2015.08.101 · DOI
  94. Suk TR, Rousseaux MWC (2020) The role of TDP-43 mislocalization in amyotrophic lateral sclerosis. Mol Neurodegener 15:45. https://doi.org/10.1186/s13024-020-00397-1 · DOI
  95. Sun Z, Brodsky JL (2019) Protein quality control in the secretory pathway. J Cell Biol 218:3171–3187. https://doi.org/10.1083/jcb.201906047 · DOI
  96. Tabas I, Ron D (2011) Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol 13:184–190. https://doi.org/10.1038/ncb0311-184 · DOI
  97. Tao YX, Conn PM (2018) Pharmacoperones as novel therapeutics for diverse protein conformational diseases. Physiol Rev 98:697–725. https://doi.org/10.1152/physrev.00029.2016 · DOI
  98. Tripathy S, Lytle KA, Stevens RD, Bain JR, Newgard CB, Greenberg AS, Huang LS, Jump DB (2014) Fatty acid elongase-5 (Elovl5) regulates hepatic triglyceride catabolism in obese C57BL/6J mice. J Lipid Res 55:1448–1464. https://doi.org/10.1194/jlr.M050062 · DOI
  99. Tripathy D, Vignoli B, Ramesh N, Polanco MJ, Coutelier M, Stephen CD, Canossa M, Monin ML, Aeschlimann P, Turberville S, Aeschlimann D, Schmahmann JD, Hadjivassiliou M, Durr A, Pandey UB, Pennuto M, Basso M (2017) Mutations in TGM6 induce the unfolded protein response in SCA35. Hum Mol Genet 26:3749–3762. https://doi.org/10.1093/hmg/ddx259 · DOI
  100. Veitia RA (2007) Exploring the molecular etiology of dominant-negative mutations. Plant Cell 19:3843–3851. https://doi.org/10.1105/tpc.107.055053 · DOI
  101. Veitia RA, Caburet S, Birchler JA (2018) Mechanisms of Mendelian dominance. Clin Genet 93:419–428. https://doi.org/10.1111/cge.13107 · DOI
  102. Vihinen M (2021) Functional effects of protein variants. Biochimie 180:104–120. https://doi.org/10.1016/j.biochi.2020.10.009 · DOI
  103. Walter P, Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334:1081–1086. https://doi.org/10.1126/science.1209038 · DOI
  104. Waterhouse A, Bertoni M, Bienert S, Studer G, Tauriello G, Gumienny R, Heer FT, de Beer TAP, Rempfer C, Bordoli L, Lepore R, Schwede T (2018) SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res 46:W296–W303. https://doi.org/10.1093/nar/gky427 · DOI
  105. Wiedemann C, Kumar A, Lang A, Ohlenschlager O (2020) Cysteines and disulfide bonds as structure-forming units: insights from different domains of life and the potential for characterization by NMR. Front Chem 8:280. https://doi.org/10.3389/fchem.2020.00280 · DOI
  106. Wilkie AO (1994) The molecular basis of genetic dominance. J Med Genet 31:89–98. https://doi.org/10.1136/jmg.31.2.89 · DOI
  107. Yang H, Hu HY (2016) Sequestration of cellular interacting partners by protein aggregates: implication in a loss-of-function pathology. FEBS J 283:3705–3717. https://doi.org/10.1111/febs.13722 · DOI
  108. Yang J, Yan R, Roy A, Xu D, Poisson J, Zhang Y (2015) The I-TASSER Suite: protein structure and function prediction. Nat Methods 12:7–8. https://doi.org/10.1038/nmeth.3213 · DOI · Paper page
  109. Yang G, Miton CM, Tokuriki N (2020) A mechanistic view of enzyme evolution. Protein Sci 29:1724–1747. https://doi.org/10.1002/pro.3901 · DOI
  110. Yang M, Luo S, Wang X, Li C, Yang J, Zhu X, Xiao L, Sun L (2021) ER-Phagy: a new regulator of ER homeostasis. Front Cell Dev Biol 9:684526. https://doi.org/10.3389/fcell.2021.684526 · DOI
  111. Yue P, Li Z, Moult J (2005) Loss of protein structure stability as a major causative factor in monogenic disease. J Mol Biol 353:459–473. https://doi.org/10.1016/j.jmb.2005.08.020 · DOI
  112. Zhang K, Kniazeva M, Han M, Li W, Yu Z, Yang Z, Li Y, Metzker ML, Allikmets R, Zack DJ, Kakuk LE, Lagali PS, Wong PW, MacDonald IM, Sieving PA, Figueroa DJ, Austin CP, Gould RJ, Ayyagari R, Petrukhin K (2001) A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy. Nat Genet 27:89–93. https://doi.org/10.1038/83817 · DOI

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Metadata

Authors
Ferrero, E., Di Gregorio, E., Ferrero, M., Ortolan, E., Moon, Y.-A., Di Campli, A., Pavinato, L., Mancini, C., Tripathy, D., Manes, M., Hoxha, E., Costanzi, C., Pozzi, E., Rossi Sebastiano, M., Mitro, N., Tempia, F., Caruso, D., Borroni, B., Basso, M., Sallese, M., & Brusco, A.
Affiliations
  • University of Turin (IT)
  • Inha University (KR)
  • Bambino Gesù Children's Hospital (IT)
  • University of Trento (IT)
  • University of Brescia (IT)
  • Neuroscience Institute Cavalieri Ottolenghi (IT)
  • Istituti Ospitalieri di Cremona (IT)
  • University of Milan (IT)
  • University of Chieti-Pescara (IT)
  • Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT)
Corresponding author
Brusco, Alfredo
ORCID
Venue
Human Genetics
Publisher
Springer Science and Business Media LLC
Published
2023-05-18
Volume
142
Issue
8
Pages
1055-1076
ISSN
  • 0018-7348 (ISSN-L)
  • 0340-6717
  • 1432-1203
DOI
10.1007/s00439-023-02572-y
PMC
PMC10449689
OpenAlex
W4377010964
Cited by
9
References
7
Citations by year
2026: 1 · 2025: 5 · 2024: 1 · 2023: 2
FWCI
1.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Human Genetics (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
  • Iris (University of Trento) (submittedVersion, cc-by)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
Funders
  • Fondazione Telethon (GGP14225, GGP12220)
  • Ministero dell'Università e della Ricerca (20203P8C3X)
  • Dipartimento di Scienze Mediche, Università degli Studi di Torino (RiLo)
  • Ministry of Education, Science and Technology (2021R1A2C1012480)
  • Università degli Studi di Torino
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
  • Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
Keywords
ELOVL5, ELOVL4, missense mutations, proteotoxicity, conformational diseases, Golgi apparatus, unfolded protein response, endoplasmic reticulum stress, Purkinje cell degeneration, neurodegeneration, protein mislocalization
MeSH terms
Fatty Acid Elongases, Amino Acid Sequence, Animals, Ataxia, Mutation, Spinocerebellar Ataxias, Mice

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