DNA Damage and Parkinson’s Disease
Abstract
:1. Introduction
2. DNA Damage and Parkinson’s Disease—The Intriguing Case of Trichloroethylene
3. Mitochondrial Dysfunction, Mitochondrial Toxins, and Parkinson’s Disease
4. Defects of Mitochondrial Pathways in Familial and Sporadic PD
5. DNA Damage in PD
6. Inflammation and PD
7. DNA Repair Deficiencies and Neurodegeneration
8. Potential Mechanisms of How DNA Damage or Repair Deficiency May Contribute to Parkinson’s Disease
9. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Chemical | Use | Mode of Action | Structure |
---|---|---|---|
MPTP | Synthetic chemical | Converted to neurotoxic MPP+ in the brain. Inhibits mitochondrial complex 1. | |
6-hydroxydopamine | Synthetic chemical used to induce Parkinsonism | Undergoes oxidation to quinones. Production of ROS. | |
Trichloroethylene | Cleaning and degreasing agent | Inhibits mitochondrial complex 1. Carcinogenic. | |
Rotenone | Insecticide, piscicide, and pesticide | Inhibits mitochondrial complex 1. | |
Paraquat | Herbicide | Production of ROS. Mitochondrial toxicity. |
Gene | Mutation Type | Mode of Action | Effect on Mitochondria | Reference |
---|---|---|---|---|
SNCA | Missense, amplification | Unknown. Disordered protein prone to aggregation | Deposition of aggregates inhibits mitochondrial function and produces ROS. | [46] |
PRKN | Missense, copy number change, LOF | Ubiquitin ligase | Promotes mitochondrial quality control. | [47] |
PINK1 | Missense, deletion, LOF | Serin/threonine protein kinase | Recruits PRKN to mitochondria. Controls respiratory chain function. | [47] |
DJ-1 | Missense, LOF | Located at outer mitochondrial membrane. | Promotes mitochondrial function. Inhibits ROS formation. | [48] |
LRRK2 | Missense, GOF | Kinase and GTPase | Promotes mitophagy. | [49] |
VPS35 | Missense, D620N, GOF (?) | Vacuolar protein sorting | Loss of VPS35 causes mitochondrial dysfunction and fragmentation. | [50] |
ATP13A2 | Missense, LOF | Lysosomal protein | Loss of ATP13A2 increases ROS and cell death. | [51] |
VPS13C | Missense, LOF | Vacuolar protein sorting | Role in normal mitochondrial biogenesis and function. | [52] |
CHCHD2 | Missense, T61I | CHCH domain containing protein | Maintains mitochondrial matrix structure. | [53] |
FBXO7 | Missense, LOF | Adapter protein for ubiquitin E3 ligase | Recruits PRKN to damaged mitochondria. | [54] |
PLA2G6 | Missense, LOF | Phospholipase | Maintains mitochondrial function. | [55] |
Gene | Name | Length | Presumed Function | Human Disorders |
---|---|---|---|---|
PRKN | Parkin | 1379 kb | Ubiquitin ligase, regulates mitochondrial quality control | Familial PD gene |
NRXN3 | Neurexin 3 | 1695 kb | Cell adhesion molecule | Autism |
OXR1 | Oxidation resistance 1 | 484 kb | Critical for oxidative stress resistance of neurons | Cerebellar hypoplasia |
RIT2 | RIC-like protein | 375 kb | Small GTPase Rit2 loss is causal for SNc cell death and motor dysfunction in mice | PD risk allele |
DLG2 | Disks large homolog 2 | 2169 kb | Synaptic protein, membrane-associated guanylate kinase | Neurodevelop-mental disorders |
LSAMP | Limbic system associated membrane protein | 644 kb | Cell adhesion molecule on axonal membranes | unknown |
RBFOX1 | RNA binding FOX1 homologue | 1692 | RNA binding protein involved in splicing | Neurodevelop-mental disorders |
VPS13B | Vacuolar protein sorting-associated 13B | 865 kb | Golgi associated protein | Autism, Cohen syndrome |
WWOX | WW domain containing oxidoreductase | 1112 kb | Multifunctional protein | Spinocerebellar ataxia, epileptic encephalopathy |
CNTNAP2 | Contactin-associated protein-like 2 | 2299 kb | Cell adhesion molecule | autism |
DAB1 | Disabled 1 | 1255 kb | Reelin signaling, critical for neurodevelopment | Neurodevelop-mental disorders |
SOX5 | SRY-related box 5 | 1033 kb | Transcription factor | Neurodevelop-mental disorder |
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Pfeifer, G.P. DNA Damage and Parkinson’s Disease. Int. J. Mol. Sci. 2024, 25, 4187. https://doi.org/10.3390/ijms25084187
Pfeifer GP. DNA Damage and Parkinson’s Disease. International Journal of Molecular Sciences. 2024; 25(8):4187. https://doi.org/10.3390/ijms25084187
Chicago/Turabian StylePfeifer, Gerd P. 2024. "DNA Damage and Parkinson’s Disease" International Journal of Molecular Sciences 25, no. 8: 4187. https://doi.org/10.3390/ijms25084187