Aspa-flox Mouse

Aspa, short for aspartoacylase, is an enzyme-encoding gene. Aspartoacylase hydrolyzes N-acetylaspartate (NAA) to acetate and aspartate [2]. Mutations in the Aspa gene lead to abnormal NAA metabolism, which is associated with Canavan disease, an autosomal recessive leukodystrophy [1,2,3].

In Canavan disease research, introducing the wild-type Aspa gene into patient-derived induced pluripotent stem cells (iPSCs) and differentiating them into neural progenitor cells (NPCs) restored Aspa enzymatic activity. When these NPCs were transplanted into CD mouse brains, they reconstituted Aspa activity, reduced the elevated NAA level in brain tissues and cerebrospinal fluid, and rescued pathological phenotypes such as spongy degeneration, myelination defects, and motor function impairment [1]. In feline spongy encephalopathy, a missense mutation in the Aspa gene was identified in affected cats, which showed similar pathological changes to human Canavan disease, suggesting that Aspa deficiency in cats also leads to spongy degeneration of the central nervous system [2]. A one-year-old female patient with Canavan disease was found to have a homozygous likely pathogenic variant in the Aspa gene, with a loss of maternal heterozygosity in the 17p13.3-p13.2 region of the gene [3].

In conclusion, Aspa is crucial for normal NAA metabolism. Gene-based research models, such as those using patient iPSCs and mouse models, have been valuable in understanding the role of Aspa in Canavan disease. These studies provide insights into the disease mechanism and potential therapeutic strategies for Canavan disease.