Niemann-Pick type C disease (NP-C) is an autosomal recessive lysosomal storage disease caused by a deficiency in either the intracellular cholesterol transporter proteins NPC1 or NPC2 (Wiweger et al., 2021). The incidence of NP-C is 1:100,000 live births, with the majority of cases caused by NPC1 deficiency (95 %), whereas NPC2 deficiency accounts for the remaining 5 % (Vanier, 2010). NPC1 is a large multidomain transmembrane protein located in the lysosomes, whereas NPC2 is a soluble sterol-binding protein targeted to the lysosomes by binding the mannose-6-phosphate receptor. The two proteins are believed to act in tandem mediating the efflux of free cholesterol and other lipids (e.g., gangliosides) from the endo-lysosomal compartment to other cellular compartments (e.g., endoplasmatic reticulum, trans-Golgi network, and plasma membrane) (Zhou et al., 2011; Li et al., 2016; Berzina et al., 2018). Mutations in the ubiquitously expressed Npc1 or Npc2 gene can lead to the loss of function or reduced activity of the gene products consequently resulting in an accumulation of cholesterol within the lysosomes (Nielsen et al., 2011; Yañez et al., 2020). Therefore, the age of onset and clinical presentation is variable and includes a diverse range of visceral manifestations such as hepatosplenomegaly with liver dysfunction, pulmonary failure, and neurological symptoms such as cerebellar ataxia, dysphagia, dysarthria, and dementia. Progressive neurodegeneration results in a fatal outcome of the disease, and most patients die before the age of 30 years (Wiweger et al., 2021; Vanier, 2010; Liu et al., 2008). While several mouse models have been established to study NP-C1, only a few murine models are available for NP-C2. Even though the pathological hallmarks are indistinguishable between the spontaneous NP-C1 (Npc1nih) mouse model and the induced NP-C2 mouse models, there are some discrepancies, e.g., when it comes to disease progression. The Npc1nih-null mouse model is more progressive, leading to earlier death (9–11 weeks of age) compared to the hypomorphic NP-C2 mouse models (12–18 weeks of age), depending on background strain (Nielsen et al., 2011; Dixit et al., 2011; Sleat et al., 2004; Loftus et al., 1997).

Two transgenic hypomorphic NP-C2 mouse models are described in the literature, the Npc2tm1Plob and the Npc2Gt(LST105)BygNya, established by targeted mutation or the gene trap approach, respectively. While the Npc2tm1Plob has been more widely used (Dixit et al., 2011; Sleat et al., 2004; Markmann et al., 2018; Roszell et al., 2013; Schrantz et al., 2007; Busso et al., 2010; Ong et al., 2004), only limited data are available for the Npc2Gt(LST105)BygNya mouse model (Nielsen et al., 2011; Schrantz et al., 2007).

Therefore, this study aimed to characterize the Npc2Gt(LST105)BygNya mouse model established on a BALB/c background with a primary focus on the pathological changes caused by NPC2 deficiency. Furthermore, a group of six-week-old mice was included to evaluate the degree of pathology before obvious symptoms are present, thereby evaluating the disease progression from six to 12 weeks of age. Finally, the pathological findings will be compared to the hallmarks of NP-C in humans to assess the translational value of this specific NP-C2 mouse model.