B6-hSNCA Mice

Figure 1. Diagram of the gene editing strategy of B6-hSNCA mice. The sequences from ATG start codon to TAA stop codon of the endogenous mouse Snca gene were replaced with the sequences from ATG start codon to TAA stop codon of the human SNCA gene by TurboKnockout targeting technology.

● Research on Parkinson's disease (PD).

1. Detection of human SNCA gene expression

Figure 2. Detection of human SNCA gene expression in the brain and spleen of wild-type mice (WT) and B6-hSNCA mice (hSNCA). The RT-qPCR analysis results showed that the human SNCA gene was expressed in both the brain and spleen of B6-hSNCA mice, while there was no expression of the human SNCA gene in WT mice, and the expression of human SNCA in the spleen was higher than that in the brain.
ND: Not detected

 

2. Detection of mouse Snca gene expression

Figure 3. Detection of mouse Snca gene expression in the brain and spleen of wild-type mice (WT) and B6-hSNCA mice (hSNCA). The RT-qPCR analysis results showed that the mouse Snca gene was expressed in both the brain and spleen of WT mice, while there was no expression of the mouse Snca gene in B6-hSNCA mice, and the expression of mouse Snca in the spleen was higher than that in the brain.

1. Basic information about the SNCA gene

https://rddc.tsinghua-gd.org/en/gene/6622

 

2. SNCA clinical variants

https://rddc.tsinghua-gd.org/en/ai/pathogenicity/result?id=fff1cfe1-2321-432f-a249-71ce03528cb0

3. Disease introduction

Parkinson’s disease is a clinically heterogeneous movement disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra and widespread deposition of Lewy bodies. PD is second only to Alzheimer's disease as the most common degenerative disease of the central nervous system. PD is currently considered to be a multifactorial disease, which may result from the interaction of various factors such as environment, aging of the nervous system, and genetics. The pathogenesis may be related to oxidative stress, mitochondrial dysfunction, and abnormal protein expression. It has been reported that 10%-15% of patients are affected by genetic factors from their immediate relatives[1].

More than 20 genes have been identified that are associated with the onset of PD. Among them, autosomal dominant mutations in SNCA, LRRK2, and VPS35, as well as autosomal recessive mutations in PINK1, DJ-1, and Parkin result in high penetrance of PD.

4. SNCA gene and mutations

The human SNCA gene is located on chromosome 4 and encodes α-synuclein. This protein is mainly expressed in brain tissue and plays an important role in synaptic signal transmission. Pathogenic mutations in SNCA cause autosomal dominant Parkinson's disease.

Research has found that in familial Parkinson’s disease, there are three SNCA gene mutations (A53T, A30P, and E46K) and the expression of its wild-type diploid. Point mutations or diploidy of the SNCA gene can cause α-synuclein protein to aggregate into Lewy bodies, hindering the metabolism of dopamine and the normal function of neurons, leading to neuronal death.

5. SNCA-targeted gene therapy

Gene therapy is one of the ways to treat PD, among which the development prospects of SNCA-targeted drugs are particularly prominent. The drug pipelines targeting SNCA are widely laid out, and ASO, siRNA, and CRISPR therapies have emerged. For example, Seelos Therapeutics’ pipeline SLS-004 is an innovative epigenetic gene editing therapy. It regulates the expression of the SNCA gene encoding α-synuclein by modulating DNA methylation. This therapy increases DNA methylation at a specific location in intron 1 of the SNCA gene, thereby precisely reducing the expression of SNCA. The preclinical study of this pipeline used humanized A53T transgenic mice[2]. It can be seen that some gene therapies based on ASO, CRISPR, and AAV have shown feasibility in basic or preliminary clinical trials.

In summary, the SNCA gene is an important pathogenic gene in Parkinson’s disease with a complex pathogenic mechanism. The SNCA whole-genome humanized model from Cyagen can be used for preclinical research on gene therapy for PD. Furthermore, Cyagen can provide customized services for different point mutations of the SNCA gene.