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PreprintCited by 7Amyotrophic Lateral Sclerosis ResearchCircular RNAs in diseasesGenomic variations and chromosomal abnormalities

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'A distinct circular DNA profile intersects with proteome changes in the genotoxic stress-related hSOD1G93A model of ALS'

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Gerovska, Daniela, Noer, Julie B, Qin, Yating, Ain, Quratul, Januzi, Donjetë, Schwab, Matthias, Witte, Otto W, Araúzo-Bravo, Marcos Jesus, Kretz, Alexandra·2023·Cell & Bioscience
DOI 10.21203/rs.3.rs-3135955/v1PMC PMC10498603

Preprint — published as 10.1186/s13578-023-01116-1 · Paper page

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Abstract

Background Numerous genes, including SOD1, mutated in familial and sporadic amyotrophic lateral sclerosis (f/sALS) share a role in DNA damage and repair, emphasizing genome disintegration in ALS. One possible outcome of chromosomal instability and repair processes is extrachromosomal circular DNA (eccDNA) formation. Therefore, eccDNA might accumulate in f/sALS with yet unknown function. Methods We combined rolling circle amplification with linear DNA digestion to purify eccDNA from the cervical spinal cord of 9 co-isogenic symptomatic hSOD1G93A mutants and 10 controls, followed by deep short-read sequencing. We mapped the eccDNAs and performed differential analysis based on the split read signal of the eccDNAs, referred as DifCir, between the ALS and control specimens, to find differentially produced per gene circles (DPpGC) in the two groups. Compared were eccDNA abundances, length distributions and genic profiles. We further assessed proteome alterations in ALS by mass spectrometry, and matched the DPpGCs with differentially expressed proteins (DEPs) in ALS. Additionally, we aligned the ALS-specific DPpGCs to ALS risk gene databases. Results We found a six-fold enrichment in the number of unique eccDNAs in the genotoxic ALS-model relative to controls. We uncovered a distinct genic circulome profile characterized by 225 up-DPpGCs, i.e., genes that produced more eccDNAs from distinct gene sequences in ALS than under control conditions. The inter-sample recurrence rate was at least 89% for the top 6 up-DPpGCs. ALS proteome analyses revealed 42 corresponding DEPs, of which 19 underlying genes were itemized for an ALS risk in GWAS databases. The up-DPpGCs and their DEP tandems mainly impart neuron-specific functions, and gene set enrichment analyses indicated an overrepresentation of the adenylate cyclase modulating g protein pathway. Conclusions We prove, for the first time, a significant enrichment of eccDNA in the ALS-affected spinal cord. Our triple circulome, proteome and genome approach provide indication for a potential importance of certain eccDNAs in ALS neurodegeneration and a yet unconsidered role as ALS biomarkers. The related functional pathways might open up new targets for therapeutic intervention.

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Metadata

Authors
Gerovska, D., Noer, J. B., Qin, Y., Ain, Q., Januzi, D., Schwab, M., Witte, O. W., Araúzo-Bravo, M. J., & Kretz, A.
Affiliations
  • Biodonostia Health Research Institute, San Sebastian, Spain
  • University of Copenhagen (DK)
  • Jena University Hospital (DE)
  • Ikerbasque (ES)
Corresponding author
  • Araúzo-Bravo, Marcos Jesus
  • Kretz, Alexandra
ORCID
Venue
Cell & Bioscience
Publisher
Springer Science and Business Media LLC
Published
2023-07-26
Volume
13
Issue
1
Pages
170-170
ISSN
2045-3701 (ISSN-L)
DOI
10.21203/rs.3.rs-3135955/v1
PMC
PMC10498603
OpenAlex
W4386712227
Cited by
7
References
1
Citations by year
2025: 3 · 2024: 2 · 2023: 2
FWCI
1.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell & Bioscience (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Common Library Network (Der Gemeinsame Bibliotheksverbund) (submittedVersion, cc-by)
Funders
  • Innovationsfonden (8088‐00049B)
  • European Commission
  • Deutsche Forschungsgemeinschaft ([WI 830/12-1], 830/12-1)
  • Carlsbergfondet (CF21-0167)
  • Else Kröner-Fresenius-Stiftung
  • Ministerio de Ciencia e Innovación (PID2020-119715GB-I00/AEI/ 10.13039/501100011033)
  • Universitätsklinikum Jena
  • Novo Nordisk Fonden (NNF21OC0072023)
  • Thüringer Ministerium für Wirtschaft, Wissenschaft und Digitale Gesellschaft (830/12-1, RegenerAging-52-5581-413-FSU-I-03/14)
  • Center for Clinical and Translational Research
  • Leibniz-Gemeinschaft
  • Instituto de Salud Carlos III
  • HORIZON EUROPE European Innovation Council (899417)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Circular RNAs in diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
Keywords
amyotrophic lateral sclerosis, extrachromosomal circular DNA, genotoxic stress, DNA damage and repair, proteome changes, differentially expressed proteins, adenylate cyclase, G protein signaling, spinal cord, ALS biomarkers, neurodegeneration

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