April 11th each year is World Parkinson's Day. Parkinson's Disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease and one of the fastest-growing neurological diseases globally. The number of patients worldwide currently exceeds 6.2 million and is rising rapidly as the population ages. Research estimates that the number of patients could surpass 25.2 million by 2050.
 

Age is the primary risk factor for PD, with an average age at diagnosis of 60. Statistics show that the prevalence of PD is about 1% in people over 60, rising to 4%-5% in those over 85. Notably, the PD patient population is trending younger, with "juvenile Parkinson's disease" patients constituting about 10% of the total.
 

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

Pathogenesis
 

The main pathological hallmark of Parkinson's Disease is the progressive loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. This leads to hypofunction of the nigrostriatal dopaminergic system. A significant reduction in striatal dopamine levels results in a relative hyperactivity of the cholinergic system, triggering a series of motor symptoms.

Image source: Animal models of Parkinson's disease: bridging the gap between disease hallmarks and research questions
 

The pathogenesis of PD is highly complex, resulting from the combined action of multiple factors, mainly including the following aspects:
 

Abnormal Aggregation of α-Synuclein (α-syn):​ This is the most distinctive pathological feature of PD. Misfolding and abnormal aggregation of α-synuclein form proteinaceous inclusions called "Lewy bodies." The accumulation of these inclusions within neurons interferes with normal cellular functions, ultimately leading to neuronal death.
 

Oxidative Stress and Mitochondrial Dysfunction:​ Dopamine metabolism itself generates free radicals, making dopaminergic neurons more susceptible to oxidative damage. Simultaneously, mitochondrial dysfunction, especially inhibition of Complex I activity, exacerbates oxidative stress, leading to an energy crisis and apoptosis in neurons.
 

Interaction of Genetic and Environmental Factors:​ The interplay between genetic and environmental factors is a crucial aspect of PD pathogenesis. Studies show that aging, genetic variations, and environmental toxins work together to cause the degeneration of dopaminergic neurons.
 

Neuroinflammation:​ During the disease process, immune cells in the brain (such as microglia and astrocytes) are abnormally activated, releasing large amounts of inflammatory factors, creating a chronic neuroinflammatory environment. This inflammatory response fails to clear pathological proteins and instead exacerbates damage to surrounding healthy neurons, forming a vicious cycle.
 

On February 20 this year, a Fudan University​ research team, through large-scale proteomic analysis, revealed early pathophysiological changes in Parkinson's Disease and their potential biomarkers, identifying early warning signals for PD in the blood. The study found that HPGDS, a protein associated with PD, was the earliest plasma protein to show abnormalities, up to 15 years before a PD diagnosis, with 16 other proteins also reaching abnormal levels defined by the researchers around 15 years before diagnosis. This discovery brings new hope for the early diagnosis and treatment of Parkinson's Disease.

Image: Temporal evolution of plasma proteins and their trajectory clusters before Parkinson's disease diagnosis
 

Analyzing Key PD-Related Genes and Mouse Models
 

Parkinson's Disease is not a single-gene disorder but a complex neurodegenerative disease triggered by the combined action of mutations or polymorphisms in multiple key genes.
 

Table 1: PD Gene-Edited Mice
 

α-Synuclein (SNCA):​ α-Synuclein (α-syn) is the main component of Lewy bodies. Its misfolding and aggregation are hallmark pathological features of PD. Missense mutations, tandem duplications, or regulatory region variations in the SNCAgene are closely associated with familial PD. Common animal models include A53T transgenic mice or mice expressing mutant α-syn under the control of the tyrosine hydroxylase (TH) promoter, which induce protein aggregation and neuroinflammation specifically in the nigrostriatal pathway. The advantage is a good simulation of α-syn-related pathology, also suitable for studying gene-environment interactions.
 

LRRK2 Gene:​ LRRK2 (leucine-rich repeat kinase 2) is currently the most common known autosomal dominant gene causing familial PD, accounting for about 4% of familial cases. Even in patients without LRRK2mutations, the protein is often hyperactivated, leading to autophagic dysfunction and abnormal α-syn accumulation. Common models include G2019S transgenic mice, which model pathological changes caused by enhanced LRRK2 kinase activity, suitable for screening candidate drugs that inhibit LRRK2 activity.
 

Parkin (PRKN) Gene:​ Parkin is a ubiquitin ligase encoded by the PRKNgene, one of the longest human genes, responsible for tagging damaged proteins for proteasomal degradation. Loss of Parkin function is the most common autosomal recessive cause of early-onset PD. Commonly used Parkinknockout mice are among the earliest genetic mouse models for PD research. These models reflect mitochondrial dysfunction and proteostasis imbalance caused by Parkin deficiency. Recent studies found that activating Parkin can improve mitochondrial function, alleviate motor symptoms, and even resist damage from neurotoxins like 6-OHDA, providing new therapeutic avenues.
 

DJ-1 Gene:​ DJ-1 is an antioxidant protein that neutralizes the oxidative microenvironment of dopaminergic neurons. Its deficiency has been confirmed as a causative factor in recessive inherited familial PD. DJ-1 deficiency exacerbates α-syn aggregation and mitochondrial abnormalities. The DJ-1KO mouse model is suitable for studying early disease stages.
 

PINK1 Gene:​ PINK1 is a key kinase involved in mitochondrial stress response and mitophagy, with mutations accounting for about 8% of early-onset familial PD cases. PINK1 functional defects lead to loss of mitochondrial quality control, triggering dopaminergic neuron degeneration. PINK1KO mouse models often show reduced dopamine levels and decreased locomotor activity, but most do not exhibit typical α-syn deposition. PINK1 models focus more on studying the link between mitochondrial dysfunction and dopaminergic system degeneration and are important tools for exploring the regulatory mechanisms of the PINK1/Parkin pathway.
 

Supporting Mechanism Research and Drug Development
 

Gene therapy offers hope for common diseases, but its development and validation rely heavily on animal model support. MingCeler Biotech, leveraging its self-developed TurboMice™ technology, has developed multiple disease mouse models. The TurboMice™ technology overcomes the technical challenges of long mouse model generation cycles and low success rates for complex models, enabling editing at almost any target gene locus. Complete homozygous gene-edited mouse models can be prepared directly from embryonic stem cells in as little as two months.
 

MingCeler Biotech​ can customize various PD-related mouse models according to client needs, such as A53T mice, LRRK2 G2019S mice, Parkin KO mice, DJ-1 KO mice, and PINK1 KO mice. Inquiries are welcome.