April 11th is World Parkinson's Day each year. Parkinson's Disease (PD) is one of the most common neurological disorders, second only to Alzheimer's disease, and is also the fastest-growing neurodegenerative disease globally. Currently, there are over 6.2 million patients worldwide, and this number is expected to exceed 25.2 million by 2050.
 

Age is the primary risk factor for Parkinson's disease, with an average diagnosis age of 60 years. Statistics show that the prevalence of PD in people over 60 is approximately 1%, rising to 4-5% in those over 85. As the population ages, the incidence of Parkinson's disease continues to increase. Additionally, Parkinson's patients are trending younger, with "juvenile Parkinson's disease" patients accounting for 10% of the total patient population.
 

Today, we will focus on Parkinson's disease and explore its pathogenesis and related animal models.

 

I. Pathogenesis
 

The main characteristic of PD is the death and loss of dopaminergic neurons in the substantia nigra of the brain, functional decline of the nigrostriatal DA system, and reduced striatal DA content leading to relative hyperactivity of the cholinergic (Ach) system.
 

The pathogenesis of PD is complex and diverse, primarily including the following aspects:

Abnormal Aggregation of α-Synuclein (α-syn): Misfolding and aggregation of α-syn form Lewy bodies, which are hallmark pathological features of Parkinson's disease. These protein aggregates interfere with normal neuronal function and ultimately lead to neuronal death.

Oxidative Stress and Mitochondrial Dysfunction: Oxidative stress and mitochondrial dysfunction are core pathological mechanisms of Parkinson's disease. Research has found that inhibition of mitochondrial complex I (as in rotenone-induced models) leads to dopaminergic neuron damage and exacerbates α-synuclein aggregation.

Interaction of Genetic and Environmental Factors: The interaction between genetic and environmental factors is an important aspect of PD pathogenesis. Studies show that aging, genetic variations, and environmental toxins collectively contribute to the degeneration of dopaminergic neurons.

Neuroinflammation: Neuroinflammation also plays a significant role in PD pathogenesis. Activation of microglia and astrocytes releases inflammatory factors that exacerbate neuronal damage.

On February 20th, a team from Fudan University revealed early pathophysiological changes and potential biomarkers of Parkinson's disease through large-scale proteomic analysis, identifying early warning signals of PD in blood. The study discovered proteins associated with Parkinson's disease, with HPGDS being the earliest plasma protein to show abnormalities up to 15 years before PD diagnosis. Another 16 proteins also reached abnormal levels defined by researchers approximately 15 years before diagnosis. This discovery brings new hope for early diagnosis and treatment of Parkinson's disease.
 

 

II.  Gene-Edited Mouse Models
 

 

α-Synuclein (α-Synuclein) is a small protein whose abnormal accumulation in the nervous system is associated with PD onset. Nonsense mutations, duplications, or mutations in regulatory regions of the SNCA gene encoding α-synuclein are closely correlated with disease development.

Leucine-Rich Repeat Kinase 2 (LRRK2) plays a key role in Parkinson's disease development. LRRK2 gene mutations account for about 4% of familial PD cases. Parkinson's patients without LRRK2 mutations also show LRRK2 protein overactivation, impaired neuronal autophagy function, leading to abnormal accumulation of α-synuclein and involvement in PD progression. Inhibiting LRRK2 activity to improve membrane transport and lysosomal function is a promising new therapeutic approach for Parkinson's disease.

Parkin, encoded by the PRKN gene, spans 1.38 million bp and is one of the largest human genes. Parkin is a ubiquitin ligase that plays a crucial role in the ubiquitin-proteasome degradation pathway, responsible for adding ubiquitin tags to unwanted proteins to guide proteasome recognition and degradation. When parkin is mutated, it cannot properly perform ubiquitination functions, leading to accumulation of cell cycle proteins or other functional proteins. In cells capable of mitosis, this causes abnormal proliferation, while in non-mitotic neurons, it leads to apoptosis. This is the most common autosomal recessive mutation in early-onset PD. Animal models with Parkin-related gene knockouts are among the earliest used PD transgenic animal models. Recent studies show that activating Parkin-related genes can improve mitochondrial function, restore PD motor symptoms, and potentially treat PD. Additionally, overexpression of Parkin-related genes protects the substantia nigra from other neurotoxins such as 6-OHDA and pathological synuclein. This discovery may provide new insights for PD treatment.

 

DJ-1 Gene Knockout Mice: Protein deglycase DJ-1 is an antioxidant protein that helps counteract the oxidative environment of DA neurons. DJ-1 deficiency has been identified as a causative factor in recessive inherited familial PD, and DJ-1 deficiency may increase α-syn aggregation and mitochondrial abnormalities in PD. DJ-1 gene knockout mice are suitable for studies targeting the early stages of phenotype induction.
 

PINK1 Gene Knockout Mice: Among all familial PD cases, PINK1 mutations account for 8% of early-onset familial PD. PINK1 is involved in mitochondrial stress response and is believed to function along the same pathway. Animal models of this gene typically do not show typical PD lesions—synuclein deposition—but exhibit mitochondrial dysfunction and degeneration of dopaminergic neurons.

 

III. Pharmacological Models
 

6-Hydroxydopamine-Induced Rat PD Model (6-OHDA) is a hydroxylated derivative of dopamine with a chemical structure similar to DA. DA neuron degeneration typically occurs within 24 hours after injection, with reduced striatal DA content appearing 2-3 days later. Successful models show 80-90% reduction in DA content, with behavioral manifestations including body tilting toward the lesioned side. This model allows quantification of PD symptom severity, partially simulates the progressive degeneration of DA neurons, and shows many similarities to human PD in pathological and biochemical aspects. Applications: Research on PD pathogenesis, drug efficacy evaluation, cell transplantation therapy, gene therapy, and neuroprotective treatments.

MPTP Animal Model (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP) is a neurotoxin primarily targeting dopaminergic (DA) neurons. This model is currently the most representative animal model of human PD characteristics. Applications: Widely used in research on PD pathogenesis, diagnosis, and treatment, contributing to the establishment of PD oxidative stress models and providing clues for studying PD cell death mechanisms.

Paraquat (PQ) Mouse Model: These neurotoxic effects of PQ exposure may mechanistically contribute to the pathogenesis of PQ-induced parkinsonism. The results of this study also strongly support the hypothesis that the increasing prevalence of Parkinson's disease is etiologically related to health risks associated with exposure to neurotoxic environmental pollutants.

Rotenone-Induced Rat PD Model: Behavioral aspects include flexed posture, reduced movement, sometimes accompanied by rigidity and tremor. Rotenone selectively causes degeneration of the nigrostriatal DA system. This model simulates PD-related characteristics well in pathology, biochemistry, pathogenesis, and behavior. However, the model preparation time is long, individual differences are significant, animal damage is substantial, and survival rates are relatively low.

 

References:

[1] Lama J, Buhidma Y, Fletcher EJR, Duty S. Animal models of Parkinson's disease: a guide to selecting the optimal model for your research. Neuronal Signal. 2021 Dec 8;5(4):NS20210026. doi: 10.1042/NS20210026. PMID: 34956652; PMCID: PMC8661507.

[2] Pang SY, Ho PW, Liu HF, et al. The interplay of aging, genetics and environmental factors in the pathogenesis of Parkinson's disease. Transl Neurodegener. 2019;8:23.

[3] Gao Y, Zhang J, Tang T, Liu Z. Hypoxia Pathways in Parkinson's Disease: From Pathogenesis to Therapeutic Targets. Int J Mol Sci. 2024;25(19):10484.

[4] Yu J, Cheng W. Large-scale proteomic analyses of incident Parkinson's disease reveal new pathophysiological insights and potential biomarkers. Nature Aging. 2025.

[5] Bloem BR, Okun MS, Klein C. Parkinson's disease. Lancet. 2021 Jun 12;397(10291):2284-2303. doi: 10.1016/S0140-6736(21)00218-X. Epub 2021 Apr 10. PMID: 33848468.

[6] Dovonou A, Bolduc C, Soto Linan V, Gora C, Peralta Iii MR, Lévesque M. Animal models of Parkinson's disease: bridging the gap between disease hallmarks and research questions. Transl Neurodegener. 2023 Jul 19;12(1):36. doi: 10.1186/s40035-023-00368-8. PMID: 37468944; PMCID: PMC10354932.

[7] Chia SJ, Tan EK, Chao YX. Historical Perspective: Models of Parkinson's Disease. Int J Mol Sci. 2020 Apr 2;21(7):2464. doi: 10.3390/ijms21072464. PMID: 32252301; PMCID: PMC7177377.

[8] Yang, Y., Shi, Y., Schweighauser, M. et al. Structures of α-synuclein filaments from human brains with Lewy pathology. Nature 610, 791–795 (2022). https://doi.org/10.1038/s41586-022-05319-3.

[9] Tong T, Duan W, Xu Y, Hong H, Xu J, Fu G, Wang X, Yang L, Deng P, Zhang J, He H, Mao G, Lu Y, Lin X, Yu Z, Pi H, Cheng Y, Xu S, Zhou Z. Paraquat exposure induces Parkinsonism by altering lipid profile and evoking neuroinflammation in the midbrain. Environ Int. 2022 Nov;169:107512. doi: 10.1016/j.envint.2022.107512. Epub 2022 Sep 8. PMID: 36108500.

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