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Cited by 51Parkinson's Disease Mechanisms and TreatmentsUbiquitin and proteasome pathwaysGenomics and Rare Diseases

A mutational atlas for Parkin proteostasis

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Clausen, Lene, Voutsinos, Vasileios, Cagiada, Matteo, Johansson, Kristoffer E., Grønbæk-Thygesen, Martin, Nariya, Snehal, Powell, Rachel L., Have, Magnus K. N. +5 more·2024·Nature Communications
DOI 10.1038/s41467-024-45829-4PMC PMC10879094

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Abstract

Proteostasis can be disturbed by mutations affecting folding and stability of the encoded protein. An example is the ubiquitin ligase Parkin, where gene variants result in autosomal recessive Parkinsonism. To uncover the pathological mechanism and provide comprehensive genotype-phenotype information, variant abundance by massively parallel sequencing (VAMP-seq) is leveraged to quantify the abundance of Parkin variants in cultured human cells. The resulting mutational map, covering 9219 out of the 9300 possible single-site amino acid substitutions and nonsense Parkin variants, shows that most low abundance variants are proteasome targets and are located within the structured domains of the protein. Half of the known disease-linked variants are found at low abundance. Systematic mapping of degradation signals (degrons) reveals an exposed degron region proximal to the so-called “activation element”. This work provides examples of how missense variants may cause degradation either via destabilization of the native protein, or by introducing local signals for degradation.

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  • Limited target length and cost considerations still impede global adoption of customised site saturation variant libraries in the field.

    “Such libraries are now favoured by many experienced MAVE laboratories (53); however, limited target length and cost considerations still impede global adoption in the field (52).”

    From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [52]

    The Methods section on site-saturation mutagenesis library cloning describes ordering and assembling a PRKN variant library, but does not discuss limits on target length, costs, or adoption across the field. Searches for those limitations returned library-preparation procedures rather than evidence for the attributed claim. (LLM, conf=0.74)

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  • Customised site saturation variant libraries eliminate codon bias, allow equal representation of each amino acid substitution, and substantially reduce the time required to optimise and implement saturation mutagenesis experiments.

    “These libraries eliminate codon bias, allow equal representation of each amino acid substitution, and substantially reduce the time required to optimise and implement saturation mutagenesis experiments.”

    From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [52]

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Authors
Clausen, L., Voutsinos, V., Cagiada, M., Johansson, K. E., Grønbæk-Thygesen, M., Nariya, S., Powell, R. L., Have, M. K. N., Oestergaard, V. H., Stein, A., Fowler, D. M., Lindorff-Larsen, K., & Hartmann-Petersen, R.
Affiliations
  • University of Copenhagen (DK)
  • University of Washington (US)
Corresponding author
Fowler, Douglas M.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-02-20
Volume
15
Issue
1
Pages
1541-1541
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-45829-4
PMC
PMC10879094
OpenAlex
W4391956897
Cited by
51
References
10
Citations by year
2026: 23 · 2025: 15 · 2024: 12 · 2023: 1
FWCI
12.62
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Novo Nordisk Fonden (PRISM, NNF21OC0071057)
  • Det Frie Forskningsråd (10.46540/2032-00007B)
  • Lundbeckfonden (R249-2017-510, R272-2017-452, R209-2015-3283)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
Parkin, proteostasis, Parkinson's disease, missense mutations, proteasomal degradation, degron, protein stability, ubiquitin ligase, genotype-phenotype correlation, nonsense mutation
MeSH terms
Proteostasis, Humans, Mutation, Proteins, Mutation, Missense, Parkinsonian Disorders, Ubiquitin-Protein Ligases

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