
Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by selective and progressive loss of dopaminergic neurons. Genetic and environmental risk factors are associated with this disease. The genetic factors are composed of approximately 20 genes, such as
Parkinson disease (PD) is the second-most common human neurodegenerative (ND) disorder after Alzheimer’s disease. The pathological features involve slow degeneration of the dopaminergic neurons in the substantia nigra (SN) and formation of intracytoplasmic Lewy body (LB) inclusion structures. Moreover, PD is characterized by neuronal inclusions composed of abnormal α-synuclein, which is generally referred to as the Lewy-related pathology (1). It leads to cellular toxicity and, eventually, PD pathogenesis. Most PD cases are idiopathic, which appears to be involved in multiple processes such as neuroinflammation, excitotoxicity, oxidative stress, environmental toxins, and accumulation of misfolded proteins from proteasome impairment (2).
Over the past 15 years, several gene mutations have been definitively shown to mediate familial PD. For instance,
Mitochondrial dysfunction and oxidative stress are the symptoms of PD pathogenesis (15). Recent demonstrations that
PD is characterized by the death of DA neurons in the substantia nigra (SN) region of the brain. Oxidative stress plays a key role in the DA neurons’ degeneration. The susceptibility of the brain, especially the SN to oxidative stress, is augmented by various factors such as high oxygen demands, higher rates of oxidative metabolism, lower levels of protective antioxidant system, and an abundant neuronal network (19). These pathways produce abundant quantities of ROS species. Moreover, mitochondrial dysfunction and the impaired protein degradation pathway align to the degeneration of dopaminergic neurons which further influence PD-related protein expressions, such as LRRK2, α-Syn, PINK1, UCH-L1, and DJ-1 (20–22). The misexpression or overexpression of the above parameters in
Most mitochondrial dysfunction results from damage to complex I or nicotinamide adenine dinucleotide phosphate (NADH): ubiquinone oxidoreductase—which forms a part of the oxidative phosphorylation system (23). PD pathogenesis results from impairment to complex I and complex I-mediated dopaminergic cell death resulting from Bax transcription activation (24). Furthermore, a clear correlation exists between ND diseases and impaired electron transport chain function. Iron containing cytochromes-associated movement plays a particularly prominent role in the mitochondrial membrane (25). As a result of this dysfunction, increased free radicals have been recorded, which is harmful to the proper functioning of cells. Oxidants, including hydrogen peroxide and superoxide radicals, are produced as byproducts of oxidative phosphorylation, making the mitochondria the main site of ROS generation within a cell. However, in pathological situations where mitochondrial respiratory defects occur, the amount of ROS produced by the electron transport chain increases dramatically, swamping the antioxidant protection mechanisms. PD has been shown to produce these conditions (Fig. 1). Evidence that oxidative stressors, such as ROS, are the culprits in these mitochondrial dysfunctions has recently emerged. The generation of oxidizing agents, such as hydrogen peroxide or superoxide, recapitulates the mitochondrial dysfunction (26).
Excess free radicals are scavenged by enzymes such as glutathione peroxidase, catalase, and superoxide dismutase in normal mitochondria. However, when ROS build up, they interact with the membrane lipids and proteins, altering their conformations and, ultimately, disrupting their functioning. Furthermore, complex I inhibitors, like MPTP or rotenone, demonstrate preferential cytotoxicity to the DA neurons (27). The MPP+ (oxidized form of MPTP that is toxic) accumulates in the mitochondria, where it inhibits complex I in the mitochondrial electron transport chain complex (METC), thereby disrupting the flow of electrons along the METC (Fig. 1). This event results in decreased ATP production and increased ROS generation (28). Similar to MPTP, rotenone is another mitochondrial complex I inhibitor. Interestingly, rotenone toxicity is involved in oxidative damage to proteins and Lewy body-like inclusions (29). Other evidence for mitochondrial dysfunction related to oxidative stress and DA cell damage comes from findings that mutations in protein genes like α
This gene encodes a putative serine/threonine kinase with a mitochondrial targeting sequence (11).
The
The most common form of sporadic PD occurs due to mutations in the gene encoding
MPTP is the most commonly used toxin to generate a PD model. It is one of the first models to link the inhibition of mitochondria complex I to PD (64). Several animal species, such as sheep, cats, mice, rats, and monkeys have been treated with MPTP to recapitulate the phenotype of a PD model. Both monkeys and mice treated with MPTP have shown selectively progressive loss of DA neurons, but no LBs (65). Loss of DA neurons leads to reduced motor abilities, although there are no LBs. MPTP induces a high level of NO in flies. Resveratrol decreases MPTP-mediated oxidative stress in flies and increases their life span. Therefore, resveratrol can be used as a therapeutic agent against PD (66), which indicates that a MPTP toxin-induced model in
Several studies have looked at rotenone and paraquat (PQ) (a proposed mitochondrial complex I inhibitor) in
Vitamin K2 acts as an electron carrier and enhances ATP production in the mitochondria. Defective mitochondria are also found in Parkinson’s patients with a
We thank Jeeyoung Lee for valuable comments. B.A. was supported by the Global Scholarship Program for Foreign Graduate Students at Kookmin University in Korea. This work is supported by grants to Y.L. from the Basic Science Research Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2016R1D1A1B 03931273 and NRF-2018R1A2B6004202).
The authors have no conflicting interests.
Parkinson’s disease and their phenotypic expressions in animal models
PD gene/locus | Mammalian/mouse | |
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Expression of Human α-Syn (A53T): ↑ Accumulation of α-synuclein, ND and leading to cell death (75). | Expression of Human α-Syn (A30P and A53T) in pan-neuron: Dopaminergic cell degeneration, LB inclusion formation and locomotor dysfunction (17). | |
Expression of Human α-Syn (A30P): Progressive motor disorder accompanied by accumulation of α synuclein in the soma and neurite (76). | ||
Expression of C-terminally truncated |
KO mutants: ↓ Lifespan and locomotion, and male sterility (40). | |
Loss of proper morphology of DA neurons and deficit in motor function (42). | ||
PARK3 | ND in SN of brain and LB formation, presence of neurofibrillary tangles and Alzheimer plaques (78). | - |
Nigral degeneration with LB, vacuoles in neurons of the hippocampus and other brain parts (78). | - | |
Rotenone induced mouse models: S-Nitrosylation of UCH-L1, ↑ α-synuclein aggregation (79). | KD mutants: ↓ Dopamine in the brain results in locomotor dysfunction (80). | |
KO mouse: Impairment in hindlimb and forelimb steps (81). | KO mutants: Mitophagy of flight muscle cells and dopaminergic neuron with aging (82). | |
KO mouse: Loss of DA neurons in SN of brain (83). | ||
Exhibit taste impairment and memory defect (59). | ||
Overexpression of |
Expression of RNA interference of JNKK or dominant-negative form of JNK increases fly survival time, locomotor activity, and decrease DA neuronal degeneration in |
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KD mouse: Impairment in lysosomal degradation, α-synuclein accumulation and neurotoxicity (85). | - | |
Unknown/PARK10 | - | - |
Heterozygous |
KO mutants: Locomotor defects and early mortality (87). | |
Unknown/PARK12 | - | - |
KO mouse: ↓ Climbing ability, movement disorders, and tremor (88). | KO mutants: Mitochondrial defects, loss of flight and climbing ability, male infertility, and increase of sensitivity to oxidative stress (89). | |
KO mouse: Loss of DA neurons in SN and rescue by feeding L-DOPA in motor dysfunction (90). | KO mutants: Mitochondrial dysfunction and oxidative stress (91). | |
KO mouse: ↓ Proteasome activities and early-onset motor deficit (92). | Expression of FBXO7 rescues |
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KD rodent: DA neuron degeneration as |
KD Mutants: DA neuron degeneration as |
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Overexpression of |
Overexpression of |
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KD of |
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Mutation in |
- | |
KO mouse: Early postnatal mortalities, and weight loss of surviving pups (96). | KD mutants: Loss of climbing abilities, decrease of lifespan, and DA neuron death (97). | |
KD mutants: ↓ Endogenous synaptic transmission at the neuromuscular junction, and 80% reduction of evoked transmission (99). |
PD genes and their phenotypic expressions in animal models, especially
PD: Parkinson’s disease, UCH-L1: ubiquitin carboxyl-terminal esterase L1, PINK1: PTEN-induced putative kinase 1, LRRK2: leucine-rich repeat kinase 2, HtrA2: High temperature requirement protein A2, FBOX7: F-box protein 7, LOF: Loss of function, KD: Knockdown, KO: Knockout, DA: dopamine, ↓: Decreased/Reduced, ↑: Increased/Enhanced, LB: Lewy body.
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