Parkinsonism Due to Mutations in PINK1, Parkin, and DJ-1 and Oxidative Stress and Mitochondrial Pathways
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Three genes have been identified that cause, in humans, autosomally inherited parkinsonism. These are PARK2, encoding the E3 ubiquitin ligase parkin; PINK1, a mitochondrial kinase; and PARK7, which codes for the protein DJ-1. In several experimental systems, it has been shown that all three proteins impact mitochondrial function and/or oxidative stress responses. These are probably related because mitochondria produce oxidative stress in neurons. Moreover, it is clear that there are relationships between these genes, with a single pathway linking PINK1 and parkin and a parallel relationship with DJ-1. Work in progress in the field is aimed at understanding these relationships in more depth.
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Loss of PINK1 is associated with mitochondrial dysfunction in Drosophila, mouse, and human.
“Loss of PINK1 has been associated with mitochondrial dysfunction in Drosophila, mouse, and human, suggesting that the roles of PINK1 in mitochondrial quality control may be evolutionally conserved [50, 51].”
From miR-27a and miR-27b regulate autophagic clearance of damaged mitochondria by targeting PTEN-induced putative kinase 1 (PINK1) (2016) · cites this paper as [51]
The PATHWAYS TO PARKINSONISM section reports mitochondrial phenotypes in PINK1-deficient Drosophila and says the human PINK1 homolog rescues them. The BIOCHEMICAL FUNCTION IN THE PINK1/PARKIN PATHWAY section also links loss of PINK1 to altered mitochondrial shape and function in cells. The passages do not establish mitochondrial dysfunction specifically in PINK1-deficient mice, so the three-species claim is only partly supported. (LLM, conf=0.83)
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References 91 · Cited by 170
Research works printed but not linked: 3
- Hardy J, Lewis P, Revesz T, Lees A, Paisan-Ruiz C. 2009. The genetics of Parkinson's syndromes: A critical review. Curr Opin Genet Dev 19: 254-265.
- Kim KY, Stevens MV, Akter MH, Rusk SE, Huang RJ, Cohen A, Noguchi A, Springer D, Bocharov AV, Eggerman TL, et al. 2011. Parkin is a lipid-responsive regulator of fat uptake in mice and mutant human cells. J Clin Invest 121: 3701-3712.
- PINK1, Parkin, and DJ-1 Cite this article as Cold Spring Harb Perspect Med 2012;2:a009415 Lavara-Culebras E, Paricio N. 2007. Drosophila DJ-1 mu- tants are sensitive to oxidative stress and show reduced lifespan and motor deficits. Gene 400: 158 -165.
- Authors
- Cookson, M. R.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Cookson, M. R.
- ORCID
- Cookson, M. R.
- Venue
- Cold Spring Harbor Perspectives in Medicine
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2012-08-22
- Volume
- 2
- Issue
- 9
- Pages
- a009415-a009415
- ISSN
- 2157-1422 (ISSN-L)
- PMC
- PMC3426824
- OpenAlex
- W2164738639
- Cited by
- 170
- References
- 91
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 7 · 2023: 10 · 2022: 12 · 2021: 11 · 2020: 13 · 2019: 15 · 2018: 13 · 2017: 10 · 2016: 17 · 2015: 10 · 2014: 18 · 2013: 18
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cold Spring Harbor Perspectives in Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Coenzyme Q10 studies and effects
- Keywords
- parkinsonism, PINK1, Parkin, DJ-1, PARK2, autosomal recessive parkinsonism, mitochondrial dysfunction, oxidative stress, E3 ubiquitin ligase, neurodegeneration
- MeSH terms
- Protein Deglycase DJ-1, PTEN-Induced Putative Kinase, Animals, Disease Models, Animal, Humans, Mitochondria, Mutation, Parkinson Disease, Protein Kinases, Signal Transduction, Oncogene Proteins, Oxidative Stress, Parkinsonian Disorders, Ubiquitin-Protein Ligases, Intracellular Signaling Peptides and Proteins, Mice
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