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Disease Models | Introduction to Animal Models of Parkinsonian Syndromes

Introduction: 

Parkinson’s disease (PD) is the most common neurodegenerative disorder of the central nervous system in middle-aged and older adults. The majority of cases are sporadic, with familial PD accounting for only a small minority. The precise etiology of PD remains unknown. Genetic factors, environmental influences, aging, oxidative stress, and other mechanisms may all contribute to the degeneration and death of dopaminergic neurons in PD. 

 

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The principal pathological changes in Parkinson’s disease are the degeneration, death, and loss of dopaminergic neurons in the midbrain, leading to impaired function of the nigrostriatal dopamine system. The reduction in striatal dopamine levels results in a relative hyperactivity of the cholinergic system. 

Therefore, there are two main approaches to establishing PD models: the neurotransmitter‑biochemical pathway and the pathological pathway. The latter more closely reflects the actual pathophysiology of PD. 

Today, we will introduce several common animal models of Parkinson’s disease. 

 

 

PD transgenic animal model

Studies have demonstrated that pathogenic genes such as α-synuclein, Parkin, DJ-1, CUH‑L1, and PINK1 are unequivocally associated with Parkinson’s disease [5][6], and transgenic animals have been generated based on this principle.

 

A53T mice: This strain is a humanized transgenic mouse, with a C57BL background.

SNCA is an autosomal dominant gene associated with Parkinson’s disease; the protein it encodes, α‑synuclein, is localized to presynaptic terminals in the central nervous system and is a soluble protein. Both point mutations in SNCA and its duplication can lead to the aggregation of α‑synuclein, disrupting dopamine metabolism and normal neuronal function, ultimately resulting in neuronal death.

Homozygous mice exhibit normal reproductive capacity, and by 8–9 months of age they gradually develop Parkinson’s disease–like phenotypes, including weight loss, tremor, and lordosis. Heterozygous mice display similar phenotypes, but with a later onset.

Immunohistochemical staining was performed on three transgenic mouse strains—4-month-old and 10-month-old—as well as their littermate negative controls. The results showed that, at 4 months of age, the α‑synuclein WT, A53T, and A30P transgenic mice did not exhibit any obvious pathological changes compared with the negative controls. 

Furthermore, immunohistochemical staining of 10-month-old transgenic mice expressing three forms of α‑synuclein revealed α‑synuclein–positive labeling, predominantly localized to glial cells and neuronal processes in the hippocampus, neocortex, and striatum. 

Structure of wild-type and A53T mutant α-synuclein in mice

 

 

DJ-1 gene-knockout mice: Mutations in the DJ-1 gene can cause early-onset, autosomal recessive Parkinson’s disease.

PINK1 gene-knockout mice: Research has shown that mutations in the PINK1 gene can lead to autosomal recessive Parkinson’s disease. Animal models carrying this genetic mutation typically do not exhibit the hallmark PD pathology—alpha-synuclein accumulation.

 

6-Hydroxydopamine–induced rat Parkinson’s disease model (6-OHDA) 

Animal selection: Healthy rats, weighing 200–250 g, of either sex. 

Construction process: Following anesthesia, rats were administered 6-hydroxydopamine (6-OHDA) into distinct regions of the substantia nigra–striatum. On postoperative days 7, 15, 22, 30, and 60, rotational behavior was assessed by subcutaneous injection of amphetamine and apomorphine at a dose of 0.05 mg/kg. At the conclusion of the behavioral testing, the animals were anesthetized, opened for thoracotomy, perfused, and their brains harvested. Brain tissue was then frozen-sectioned, and neuronal Nissl staining and immunohistochemical staining were performed. 

Model features: This model is an acute injury model. 6-OHDA is a hydroxylated derivative of dopamine, with a chemical structure similar to DA. Typically, degeneration of dopaminergic neurons becomes apparent 24 hours after injection, and a reduction in striatal DA levels occurs within 2–3 days. In successful models, DA levels decrease by 80%–90%, and behavioral manifestations include ipsilateral body tilting toward the lesioned side. The model allows for quantitative assessment of PD symptom severity, partially mimics the progressive degeneration of dopaminergic neurons, and exhibits pathophysiological and biochemical features that closely resemble those of human PD. 

Purpose: Research on the pathogenesis of Parkinson’s disease, evaluation of drug efficacy, cell transplantation therapy, gene therapy, and neuroprotective treatments. 

 

 

MPTP animal model (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP)

Animal selection: Adult rhesus monkeys, adult cynomolgus monkeys, and adult squirrel monkeys, with a body weight of approximately 4.5 kg; C57 mice, 10–12 weeks old, weighing 25–30 g; adult domestic cats, with a body weight of about 2.5 kg, and other laboratory animals. 

Construction process: It is divided into a bilateral lesion–based PD model‑construction method and a unilateral lesion–based PD model‑construction method. 

 

Method for constructing a bilateral lesion Parkinson’s disease model:

The method for constructing non-human primate models is as follows: MPTP was administered via intravenous injection into the lower limbs, with three injections on the first day and two injections per day on the second and third days.

The construction methods for mice and cats are as follows: MTPT was administered by intraperitoneal injection to mice for 7 consecutive days and to domestic cats for 5 consecutive days.

Following drug administration, the animals’ behavioral activity was monitored. At postoperative days 10, 14, and 21, the animals were euthanized, and brain tissues were collected for immunohistochemical staining.

Immunohistochemical staining results

Principle of the MPTP Model

 

Model features: MPTP is a neurotoxin that primarily targets dopaminergic neurons and exhibits toxic effects in a wide range of species, including primates, cats, rodents, dogs, sheep, frogs, and goldfish. Among these, primates are the most sensitive to MPTP, whereas mice and other animals display greater resistance; however, due to animal‑ethics review requirements, mice are commonly used for model‑generation.

This model is currently the most representative animal model of human Parkinson’s disease. 

Purpose: It is widely employed in research on the pathogenesis, diagnosis, and treatment of Parkinson’s disease, facilitating the establishment of oxidative stress–based PD models and providing valuable insights into the mechanisms of PD‑related cell death. 

Special Note: Mice exhibit strain- and age-dependent differences in susceptibility to MPTP; in comparison, C57BL mice are the most sensitive, and older mice display greater sensitivity than younger ones. 

MPTP is highly toxic; it should be prepared fresh as needed, and laboratory personnel must take appropriate personal protective measures. 

 

 

Rotenone-Induced Rat Model of Parkinson’s Disease

Animal selection: Lewis rats, weighing 300–350 g. 

Construction process: Following injection anesthesia, an osmotic micro‑pump was implanted subcutaneously in the back, with its infusion line connected to a jugular vein at the mandibular angle. Rotenone was infused daily, and the pump was replaced monthly, for a total duration of 5 weeks. 

Model features: In terms of behavior, animals exhibit a flexed posture and reduced locomotion, sometimes accompanied by rigidity and tremor. Rotenone can selectively induce degeneration of the nigrostriatal dopamine system. This model effectively mimics key features of Parkinson’s disease across pathological, biochemical, pathogenic, and behavioral domains. However, it requires a lengthy preparation process, shows substantial inter‑individual variability, causes considerable animal distress, and has a relatively low survival rate. 

 

References:

[1]Sherer TB, Betarbet R, Greenamyre JT. Environment, mitochondria, and Parkinson's disease[J]. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry. 2002,8(3):192-7.

[2] Methodology for the Replication of Animal Models of Human Diseases / Edited by Zhou Guangxing et al. — Shanghai: Shanghai Scientific & Technological Literature Publishing House, Jan. 2008.

[3]Jackson-Lewis V, Przedborski S. Protocol for the MPTP mouse model of Parkinson’s disease. Nat Protoc. 2007;2(1):141–51.

[4]Blum, D., Torch, S., Lambeng, N., Nissou, M., Benabid, A. L., Sadoul, R., & Verna, J. M. (2001). Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson's disease. Progress in neurobiology, 65(2), 135–172.

[5]Cookson MR. Pathways to parkinsonism[J].Neuron,2003,37(1):7-10.

[6]Valente EM,Abou-Sleiman PM,Caputo V,et al.Hereditary early-onset Parkinson′s disease caused by mutations in PINK1 [J]. Sci-ence,2004,304(5674):1158-1160.

[7]http://omim.org/entry/163890?search=SNCA&highlight=snca

[8]Orkid Coskuner 1, Olivia Wise-Scira. Structures and free energy landscapes of the A53T mutant-type α-synuclein protein and impact of A53T mutation on the structures of the wild-type α-synuclein protein with dynamics. ACS Chem Neurosci[J]. 2013 Jul 17;4(7):1101-13. 

 

 

Aniphe BioLab can provide PD animal model mice— A53T mouse 。

Now on a rock-bottom price promotion: originally 2,500 yuan per unit, now only… 900 yuan per unit , Welcome to inquire!

A PD animal model has been established, supported by a comprehensive research service platform that includes upstream and downstream monitoring as well as pharmacological and pharmacodynamic evaluation services.

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