Spinocerebellar ataxias (SCAs) are a group of genetic diseases that mainly manifest as chronic progressive ataxia, such as limping, sudden falls, and difficulty in pronunciation. The main lesion sites of these diseases are the cerebellum and its associated tissues. They are mostly inherited in an autosomal dominant manner, but there are also autosomal recessive and X-linked inheritance types. The average incidence of SCA is 2.7 per 100,000 people ^[1]. SCA can be divided into repeat expansion type and non-repeat expansion type according to the genetic mutation type. Among them, repeat expansion type includes polyglutamine SCA and non-translated region repeat expansion type SCA. Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), belongs to polyglutamine SCA and is the most common dominant hereditary ataxia. The pathogenesis of SCA3 is the loss of neurotransmitters caused by CAG repeat expansion in the ATXN3 gene. This expansion results in a long polyglutamine (polyQ) domain in the Ataxin 3 protein, leading to protein aggregation and dysfunction of the ubiquitin-proteasome system. The CAG repeat number in the healthy human ATXN3 gene ranges from 12 to 44, while the polyQ domain of SCA3 patients abnormally increases, with CAG repeat numbers ranging from 56 to 87. Individuals with CAG repeat numbers between 45 and 55 exhibit incomplete penetrance of SCA3 symptoms. Like other PolyQ diseases, the CAG repeat number is negatively correlated with the age of onset of SCA3 and positively correlated with the severity of the disease ^[2-3]. Currently, most SCA treatments targeting the ATXN3 gene are in the early stages of development and mainly involve reducing abnormal ATXN3 expression through means such as miRNA or ASO drugs. The Ataxin 3 protein in mice does not contain or only contains a shorter polyQ structure. Considering the differences between humans and mice in terms of genes, humanizing mouse genes can help accelerate these treatments into clinical stages. This strain is a mouse Atxn3 gene humanized model that can be used for research on Spinocerebellar ataxia type 3 (SCA3) ^[4-9]. The homozygous B6-hATXN3 mice are viable and fertile. Additionally, based on the independently developed TurboKnockout fusion BAC recombination technology, Cyagen can also generate hot mutation models based on this strain and provide customized services for specific mutations to meet experimental needs in pharmacology.

The ATXN3 gene encodes Ataxin 3, a protein primarily responsible for intracellular protein degradation and involved in various cellular processes including DNA repair and autophagy. The ATXN3 gene is widely expressed in the human brain and other tissues, with particularly high expression levels in the cerebellum and spinal cord ^[1]. Spinocerebellar Ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD), is a progressive neurodegenerative disorder characterized clinically by motor coordination impairment (cerebellar ataxia), bulbar, pyramidal, and extrapyramidal dysfunction, and may be accompanied by peripheral neuropathy or ophthalmoplegia ^[2]. SCA3 is the most common dominantly inherited ataxia, caused by an abnormal expansion of CAG repeat sequences in the ATXN3 gene. This expansion leads to the formation of an elongated polyglutamine (polyQ) domain in the Ataxin 3 protein, subsequently causing protein aggregation and dysfunction of the ubiquitin-proteasome system. Among polyglutamine diseases, the prevalence of SCA3 is second only to Huntington's disease (HD). The number of CAG repeats in the ATXN3 gene of healthy individuals typically ranges from 12 to 44, whereas affected individuals with SCA3 have 56 to 87 repeats. Individuals with 45 to 55 repeats may exhibit incomplete penetrance of SCA3 symptoms. Similar to other polyglutamine diseases, the length of the CAG repeat is negatively correlated with the age of onset and positively correlated with the severity of SCA3 ^[2-3]. This strain represents a SCA3 disease model generated through transgenic technology, expressing a human ATXN3 gene carrying approximately 85 CAG repeats (Q). The number of CAG repeats (Q) in the human ATXN3 gene in this model is associated with the more severe forms of SCA3. Preliminary research data indicate that 2-month-old TG-hATXN3(85Q) mice exhibit a significant increase in stride width and a shortened latency to fall in the rotarod test, suggesting impairments in motor coordination and activity. Therefore, this strain can be utilized for research on the ubiquitin-proteasome system and the pathogenic mechanisms of SCA3, as well as for the screening, development, and evaluation of targeted therapeutic drugs.

Sftpd is located on chromosome 14 of mice. Nuclease Technology was used to design sgRNA; Sftpd knockout mice were obtained by applying high-throughput electroporation of fertilized eggs. After sexual maturity, sperm were collected for cryopreservation.

Pip5k1a is located on chromosome 3 of mice. SgRNA and ssDNA were designed using Nuclease Technology; Pip5k1a conditional knockout mice were obtained by high-throughput electroporation of fertilized eggs. After sexual maturity, sperm were collected for cryopreservation.