Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is a fatal progressive neurodegenerative disease. The disease is caused by the degeneration and death of motor neurons that control skeletal muscles in the central nervous system, leading to gradual muscle weakness and atrophy, and ultimately complete loss of voluntary movement control by the brain ^[1]. Unlike Alzheimer’s disease, ALS does not necessarily affect higher brain functions. On the contrary, late-stage patients can maintain clear thinking and retain memories, personality, and intelligence before the onset of the disease. The known ALS-causing genes include SOD1, ALS2, TARDBP, and FUS, among others.

FUS is a multifunctional DNA/RNA-binding protein that is usually localized within the nucleus but can also shuttle between the nucleus and the cytoplasm. The FUS protein plays an important role in processes such as RNA transcription, splicing, and microRNA processing. Mutations in the FUS gene are closely associated with frontotemporal lobar degeneration/dementia (FTLD-FUS) and amyotrophic lateral sclerosis (ALS-FUS). Typically, the histopathological feature of ALS-FUS patients is the mislocalization of the FUS protein to the cytoplasm in spinal cord neurons and glial cells, and the formation of FUS-positive inclusions. However, based on current cases, only a portion of patients exhibit FUS mislocalization, and changes in the nuclear function of FUS mutants can also trigger ALS. Pathological FUS mice can induce neurodegeneration in the absence of cytoplasmic pathological changes or even significant mislocalization, which strongly indicates that the toxic nuclear function of FUS mutants may be a potential pathogenic mechanism. More than 50 FUS gene mutations have been found in patients with familial ALS and sporadic ALS, and the vast majority of them are inherited in an autosomal dominant pattern ^[2]. The mutant FUS protein generated by the R521C mutation in the FUS gene can form a stable complex with the wild-type (WT) FUS protein, interfere with normal protein interactions, cause DNA damage, and exhibit abnormal dendritic and synaptic phenotypes in the mouse brain and spinal cord. There is evidence that FUS-R521C mice have defects in transcription and splicing of genes responsible for regulating dendritic growth and synaptic function ^[3].

The FUS-targeted drugs under research are mainly gene therapy drugs, such as antisense oligonucleotides (ASOs). The ASO drug (ION363) developed by Ionis has entered phase 3 clinical trials. This drug can effectively reduce the abnormal expression of FUS in diseased mice ^[4]. Most gene therapy methods act on human genes. Considering the genetic differences between animals and humans, humanizing the mouse genes will help accelerate the advancement of FUS-targeted gene therapies into the clinical stage. This model is a humanized model. Gene editing technology is used to replace the endogenous mouse Fus gene with a human FUS gene fragment carrying the R521C mutation. B6-hFUS*R521C mice can be used for the research of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration/dementia (FTLD). In addition, based on the technological innovation of TurboKnockout fusion BAC recombination independently developed by Cyagen, customized services can be provided for different point mutations to meet the experimental needs of researchers.