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Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease[1], and the number of patients with Parkinson's disease is huge. Data show that there are more than 2.7 million Parkinson's disease patients in my country, and the number of new patients each year reaches 100,000. above. The prevalence rate of people over 65 years old is 1%-2%, and the prevalence rate of people over 85 years old is even as high as 4% [2]. The incidence of the disease is expected to double within the next 20 years as the proportion of the elderly population in the world grows [3]. Parkinson's disease is characterized by resting tremor, bradykinesia, stiffness, and other quality-of-life-reducing symptoms that ultimately lead to severe disability due to the inability to control motor function [2]. It is characterized by early degeneration and death of dopaminergic neurons in the substantia nigra pars compacta (SNpc), and widespread accumulation of α-synuclein (α-Syn) in the cells.
Figure 1: Schematic of several regions of the brain that are adversely affected in Parkinson's disease (PD).
Oxidative stress is caused by the imbalance of oxidation and anti-oxidation in the body. Under the influence of oxidative stress, the body will produce a large number of active oxygen free radicals, triggering cell damage. In recent years, many clinical literature reports have confirmed that oxidative stress is closely related to the occurrence and development of Parkinson's disease[5]. Studies have confirmed that the generation of active oxygen free radicals will lead to the loss of dopaminergic neurons in the brains of patients with Parkinson's disease; and the reduction of dopamine metabolism and glutathione levels can lead to a large number of active oxygen free radicals. It has been confirmed that the inhibition of mitochondrial complex Ⅰ will also affect the synthesis of reactive oxygen free radicals, and reactive oxygen free radicals can cause mitochondrial DNA (mtDNA) damage. Neurons have certain high metabolic characteristics, and they bear a high oxidative burden. Therefore, as the degree of oxidative stress increases, the degree of damage to neurons by dopamine in the substantia nigra will also increase significantly.
In patients with Parkinson's disease, solubleα-Syn monomers initially form oligomers, which gradually combine to form small fibrils and finally form large and insolubleα-Syn fibrils (i.e., constituting the major components of Lewy bodies)[6], The formation of Lewy bodies in the substantia nigra pars compacta in a specific brain region of the midbrain is one of the main pathological features of primary Parkinson's disease [7].
In addition, toxic oligomers can activate microglia, induce neuroinflammation, and eventually lead to the occurrence of Parkinson's disease [8]. It has been proven that the main pathological features of Parkinson's disease can be reproduced in the mouse model ofα-Syn [9].
Neuroinflammation is one of the hallmarks of Parkinson's disease, and there is a close relationship with genes associated with Parkinson's disease risk, such as LRRK2. Experiments have shown that neuroinflammation can promote misfolding and aggregation of α-Syn to induce Parkinson's disease innate immunity and adaptive immunity [10]. Studies suggest that tissue inflammation in the olfactory system or in the gut can trigger higher levels of α-Syn misfolding, making some α-Syn aggregates eventually escape the normal degradation mechanism[11]. Experimental evidence by Sampson et al. The tract microbiota plays an important role in promoting microglial activation and α-Syn pathology as well as motor deficits [12].
Table1: Routes of administration and pathological mechanisms of dopaminergic neurotoxins
| Model Name | Modeling Method | Advantages / Disadvantages | |
| Nerve Injury Model |
6-OHDA Model | It is usually injected into the substantia nigra of male SD rats by stereotaxic injection | One-sided modeling and two-sided modeling are available for easy comparison |
| MPTP Model | intraperitoneal injection of MPTP | Low mortality rate, may help to resume different stages of PD and better understand the pathophysiology of the disease | |
| Rotenone Model |
Injection methods can be divided into subcutaneous injection, intraperitoneal injection, intravenous injection and striatal localized injection | Enhanced oxidative stress and neuroinflammation in the DA pathway, covering most of the pathological features of PD. | |
| LPS | Brain targeting injection (intrasnigral, globus pallidus, striatal ventricle) | It can show the body's inflammatory response caused by excessive activation of microglia and the selective damage characteristics of DA neurons in the nigrostriatal system. |
|
| MFB | The death of dopamine neurons in the midbrain of rats by cutting MFB with a wire knife | The success rate is high and the experiment cost is low. At the same time, it can better simulate the degeneration and necrosis of dopaminergic neurons in the SNc site. | |
| Transgenic model |
LRRK2 | LRRK2 is a multidomain protein located on the cell membrane. The likelihood of developing PD with LRRK2 gene mutations increases with age. | The inadequacy of the LRRK2 model is that it cannot mimic the neuronal cell death characteristic of PD. |
| α-Syn | Abnormal α-Syn can lead to dopaminergic neuronal degeneration in familial PD | Different promoter regulation can simulate the pathological manifestations of PD to different degrees | |
| Parkin | Parkin-Q311X transgenic mice overexpressing mutant Parkin proteins exhibit DA neuronal degeneration | There are six gene mutations related to PD that have been reported, and each gene has a corresponding transgenic PD model. |
Literature citation
[1] Spatola M, Wider C. Genetics of Parkinson’s disease: the yield[J]. Parkinsonism & Related Disorders, 2014, 20: S35-S38.
[2] Harris M K, Shneyder N, Borazanci A, et al. Movement disorders[J]. Medical Clinics of North America, 2009, 93: 371-388.
[3] Chen J J. Parkinson’s disease: health-related quality of life, economic cost, and implications of early treatment[J]. The American Journal of Managed Care, 2010, 16:S87-S93.
[4] Kin K, Yasuhara T, Kameda M,et al. Animal Models for Parkinson's Disease Research: Trends in the 2000s [J]. International Journal of Molecular ences, 2019, 20(21):5402.
[5] 赵颖,戴惟葭,刘大川.不同程度帕金森病患者视盘参数及视网膜神经纤维层厚度定量分析[J].中华眼底病杂志,2020,36(1):15-19
[6] Melki R. Role of different alpha-synuclein strains in synucleinopathies, similarities with other neurodegenerative diseases[J]. Journal of Parkinson’s Disease, 2015, 5(2): 217-227.
[7] 陈加俊, 田明秀, 李兴安, 等. 帕金森病路易(小)体的蛋白质生物信息学数据分析[J]. 生物化学与生物物理进展,2013, 40 (11): 1100-1106.
[8] 游静, 顾乔乔, 余子云, 等. 帕金森病发病机制的研究进展[J]. 赣南医学院学报,2019, 39 (7): 733-737.
[9] Hasegawa M,Nonaka T,Masuda-Suzukake M.Prion-like mechanisms and potential therapeutic targets in neurodegenerative disorders[J]. Pharmacology & Therapeutics, 2017, 172:22-33.
[10] Gao H M, Kotzbauer P T, Uryu K, et al. Neuroinflammation and oxidation/nitration of alpha-synuclein linked to dopaminergic neurodegeneration.[J]. Journal of Neuroscience, 2008, 28(30): 7687-7698.
[11] Carla M L T, Tyson T, Rey N L, et al. Inflammation and α-synuclein’s prion-like behavior in Parkinson’s disease--is there a link?[J]. Molecular Neurobiology, 2012, 47(2): 561-574.
[12] Sampson T, Debelius J, Thron T, et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease[J]. Cell, 2016, 167(6): 1469-1480.
In the field of drug efficacy and pharmacological evaluation related to neurological diseases, Brrain Case can provide you with a one-stop platform for evaluating the behavior of animals from the gene molecular level to the cell tissue level, to the neural circuit, and finally to the animal as a whole.
At the gene molecular level, through gene editing, gene interference, in situ hybridization, immunohistochemistry and other technical means, verify the influence of genes or proteins on cell physiological metabolic signal transduction, gene expression regulation, etc. Experimentally verify the function of a molecule.
At the neural circuit level, we can analyze the structure and function of neural circuits formed between different brain regions and different types of neurons by means of circuit tracing, optogenetics, chemical genetics, and electrophysiology. Such research is one of the key development directions of neuroscience at present. Understand, manipulate and analyze the dramatic phenotypic differences brought about by changes in neuronal connectivity.
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