Cited by 89Parkinson's Disease Mechanisms and TreatmentsUbiquitin and proteasome pathwaysNuclear Receptors and Signaling
Structural and Functional Impact of Parkinson Disease-Associated Mutations in the E3 Ubiquitin Ligase Parkin: HUMAN MUTATION
Open accessFiesel, Fabienne C., Caulfield, Thomas R., Moussaud-Lamodière, Elisabeth L., Ogaki, Kotaro, Dourado, Daniel F.A.R., Flores, Samuel C., Ross, Owen A., Springer, Wolfdieter·2015·Human Mutation
DOI 10.1002/humu.22808PMC PMC4514554
Abstract
Mutations in the PARKIN/PARK2 gene that result in loss-of-function of the encoded, neuroprotective E3 ubiquitin ligase Parkin cause recessive, familial early-onset Parkinson disease. As an increasing number of rare Parkin sequence variants with unclear pathogenicity are identified, structure-function analyses will be critical to determine their disease relevance. Depending on the specific amino acids affected, several distinct pathomechanisms can result in loss of Parkin function. These include disruption of overall Parkin folding, decreased solubility, and protein aggregation. However pathogenic effects can also result from misregulation of Parkin autoinhibition and of its enzymatic functions. In addition, interference of binding to coenzymes, substrates, and adaptor proteins can affect its catalytic activity too. Herein, we have performed a comprehensive structural and functional analysis of 21 PARK2 missense mutations distributed across the individual protein domains. Using this combined approach, we were able to pinpoint some of the pathogenic mechanisms of individual sequence variants. Similar analyses will be critical in gaining a complete understanding of the complex regulations and enzymatic functions of Parkin. These studies will not only highlight the important residues, but will also help to develop novel therapeutics aimed at activating and preserving an active, neuroprotective form of Parkin.
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The machine-learning classifier had excellent agreement with the established GFP-PRKN ratio algorithm and a combined Z' score of 0.79.
“There was excellent agreement between the new classifier and the established ‘GFP-PRKN ratio’ algorithm [19, 20, 25, 30] (Fig. 1C, Table S4) but the new classifier was more robust in this screening setting and had a combined Z’ score of 0.79.”
From miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A (2026) · cites this paper as [25]
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- Authors
- Fiesel, F. C., Caulfield, T. R., Moussaud-Lamodière, E. L., Ogaki, K., Dourado, D. F. A. R., Flores, S. C., Ross, O. A., & Springer, W.
- Affiliations
- Mayo Clinic (US)
- Uppsala University (SE)
- Corresponding author
- Springer, Wolfdieter
- ORCID
- Venue
- Human Mutation
- Publisher
- Wiley
- Published
- 2015-06-03
- Volume
- 36
- Issue
- 8
- Pages
- 774-786
- ISSN
- 1059-7794 (ISSN-L)
- PMC
- PMC4514554
- OpenAlex
- W1894946963
- Cited by
- 89
- References
- 60
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 15 · 2023: 1 · 2022: 7 · 2021: 12 · 2020: 9 · 2019: 8 · 2018: 14 · 2017: 9 · 2016: 8 · 2015: 1
- FWCI
- 7.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Human Mutation (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS085070, NS072187)
- Michael J. Fox Foundation for Parkinson's Research
- Mayo Clinic
- Wenner-Gren Foundation
- Center for Individualized Medicine, Mayo Clinic
- eSSENCE
- Foundation for Mitochondrial Medicine
- Gerstner Family Foundation
- Marriott Family Foundation
- Swedish National Infrastructure for Computing (SNIC) at UPPMAX
- Uppsala University
- 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 › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- Parkin, PARK2, Parkinson's disease, E3 ubiquitin ligase, missense mutations, loss-of-function mutations, protein folding, protein aggregation, autoinhibition, protein solubility, structure-function analysis, pathogenicity assessment, neuroprotection
- MeSH terms
- HeLa Cells, Humans, Models, Molecular, Mutation, Parkinson Disease, Protein Isoforms, Ubiquitin-Protein Ligases
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