Animal models of Parkinson's disease
Parkinson's disease is a neurodegenerative disorder, characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc).
The loss of the dopamine neurons in the brain, results in motor dysfunction, ultimately causing the four cardinal symptoms of PD: tremor, rigidity, postural instability, and bradykinesia.
[4] Through scientific studies, this neurotoxin has been used in rodents (rats and mice), guinea pigs, cats, dogs, and monkeys.
However, injections into the SNpc is estimated to degrade about 60% of tyrosine hydroxylase (TH+) neurons as well as loss of TH positive terminals in the striatum.
A limitation to using 6-OHDA is that the potency of the neurotoxin causes rapid apoptosis, which makes it difficult to study Parkinson's disease progression.
There is also oxidative stress occurring mediated through the inhibition of the cell's mitochondrial complex I, producing ROS (reactive oxygen species), which causes a decrease or loss in respiratory activity.
This neurotoxin is known to replicate oxidative stress, ROS, energy failure, and inflammation; which are all hallmarks in Parkinson's disease.
Once released into the extracellular space, MPP+ is taken up into the neuron by DAT and is stored in vesicles by the up take of vesicular monoamine transporter (VMAT2).
In the neuron, MPP+ inhibits the function of complex 1 of electron transport chain, which decreases ATP production and releases ROS.
Rotenone is a chemical compound (Figure 6) that can be derived from the plants: Derris elliptica, D mallaccensis, Lonchocarpus utilis, and L urucu.
However, since it is capable to cross the BBB, the toxin can be found in other regions such as the pineal gland, cerebral ventricles, olfactory bulb, hypothalamus, and the area postrema.
[9][10] Alpha-synuclein (α-synuclein) is an endogenous protein that is encoded by the SNCA gene and known as the pathological hallmark of Parkinson's disease.
In addition, studies have shown that there is progressive formation of α-synuclein inclusions in distinct brain areas like the hippocampus, the cortex, and amygdala.
Moreover, the spread of α-synuclein PFFs to brain regions occur through the uptake of the fibrils by dopamine neuron terminals that make their way up to the soma in the SNpc (Figure 9).
[11] The different synuclein models that have been widely used have also faced challenges of targeting the fibrils to the SNpc, thus, lacking abundant neurodegeneration.
It is still unclear as to the mechanism of action of LRRK2, however, the kinase activity is of importance and its ability to function as a GTPase is also a factor in its neurotoxicity.
Similar to other genetic animal models, LRRK2 mutations also produce dopaminergic neuron loss in the substantia nigra and Lewy body pathology.
LRRK2 knockout models have also been studied and show the increase of protein aggregation and accumulation which also includes α-synuclein; but, it does not decrease degeneration of nigrostriatal neurons.
[19] Some studies have demonstrated expression of the PINK1 mutation in rodents, inducing dopaminergic neuron loss and motor defects.
[14] It is a molecular chaperone that undergoes reduction-oxidation (redox) reaction and plays a major role in the inhibition of alpha synuclein aggregate formation.
To demonstrate the proposed neuroprotective properties of DJ-1, knockout studies of this gene have shown motor deficits in mice, less dopamine levels in the striatum, and no evidence of Lewy body aggregation.
[19] Table 1[8][6][22][11] represents a summary of the PD animal models and details regarding their mechanisms of action, pathogenesis, and limitations.
