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PreprintCited by 9Genetic Neurodegenerative DiseasesHereditary Neurological DisordersLysosomal Storage Disorders Research

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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, Gregorio, Eleonora Di, Ferrero, Marta, Ortolan, Erika, Moon, Young-Ah, Campli, Antonella Di, Pavinato, Lisa, Mancini, Cecilia, Tripathy, Debasmita, Manes, Marta, Hoxha, Eriola, Costanzi, Chiara, Pozzi, Elisa, Sebastiano, Matteo Rossi, Mitro, Nico, Tempia, Filippo, Caruso, Donatella, Borroni, Barbara, Basso, Manuela, Sallese, Michele, Brusco, Alfredo·2023·Human Genetics
DOI 10.21203/rs.3.rs-2616059/v1PMC PMC10449689

Preprint — published as 10.1007/s00439-023-02572-y · Paper page

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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 disulfide 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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Metadata

Authors
Ferrero, E., Gregorio, E. D., Ferrero, M., Ortolan, E., Moon, Y.-A., Campli, A. D., Pavinato, L., Mancini, C., Tripathy, D., Manes, M., Hoxha, E., Costanzi, C., Pozzi, E., Sebastiano, M. R., Mitro, N., Tempia, F., Caruso, D., Borroni, B., Basso, M., Sallese, M., & Brusco, A.
Affiliations
  • University of Turin (IT)
  • Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT)
  • Istituto Zooprofilattico Sperimentale del Piemonte Liguria e Valle d'Aosta
  • Inha University (KR)
  • University of Chieti-Pescara (IT)
  • 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)
Corresponding author
Brusco, Alfredo
ORCID
Venue
Human Genetics
Publisher
Springer Science and Business Media LLC
Published
2023-02-28
Volume
142
Issue
8
Pages
1055-1076
ISSN
0018-7348 (ISSN-L)
DOI
10.21203/rs.3.rs-2616059/v1
PMC
PMC10449689
OpenAlex
W4377010964
Cited by
9
References
1
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
  • Dipartimento di Scienze Mediche, Università degli Studi di Torino
  • Fondazione Telethon (GGP12220, GGP14225)
  • National Research Foundation of Korea (2021R1A2C1012480)
  • Ministry of Education, Science and Technology (2021R1A2C1012480)
  • Università degli Studi di Torino
  • Ministero dell'Università e della Ricerca (20203P8C3X)
  • Ministerio de Universidades
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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