huSTMN2 Mouse

The STMN2 gene encodes the stathmin-2 protein, a microtubule-associated protein and member of the stathmin family. It plays a critical role in neuronal development, axonal growth, and regeneration by regulating microtubule dynamic stability. The STMN2 gene is predominantly expressed in the nervous system, with the highest levels in central and peripheral neurons, serving as a key molecule for maintaining axonal integrity and regenerative capacity. Additionally, its expression is elevated in developing neurons and is also present at moderate levels in adult brain tissues and the adrenal gland. Studies have shown that loss of TDP-43 function leads to cryptic splicing or premature polyadenylation of STMN2 mRNA, resulting in a significant reduction in functional STMN2 protein levels. This, in turn, causes neuromuscular junction denervation and axonal degeneration, which can be effectively reversed by exogenous supplementation of STMN2 or its post-translational stabilization ^[1-2]. In clinical research, the reduction of STMN2 due to TDP-43 pathology is a common feature in the majority of patients with amyotrophic lateral sclerosis (ALS) and can serve as a disease biomarker and potential therapeutic target ^[3]. Furthermore, STMN2 regulates α-synuclein (α-syn) aggregation and dopaminergic axonal integrity. It is significantly downregulated in the brain tissue of patients with Parkinson’s disease (PD), leading to dopaminergic neuron degeneration, elevated phosphorylated α-syn, and motor deficits. It has been identified as a key regulator functionally connected to known PD risk genes ^[4-5]. Studies have shown that humanized mouse models can precisely recapitulate STMN2-related pathological mechanisms. By delivering shRNA via adeno-associated virus (AAV), these models enable central nervous system-specific regulation, providing a robust tool platform for investigating the mechanisms of Parkinson’s disease (PD) ^[6].

The huSTMN2 mouse is a humanized model constructed using gene editing technology. The sequences from upstream of the exon 1 to downstream of the exon 5 of the mouse Stmn2 were replaced with the sequences from upstream of the exon 1 to downstream of the exon 5 of the human STMN2. The huSTMN2 mice can be used to investigate the pathogenesis and progression of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD), facilitating the research and development of STMN2-targeted drugs and gene therapy strategies, as well as preclinical pharmacological and efficacy evaluations.