Details

Autor(en) / Beteiligte

• Rasmussen, Charlotte Laurfelt Munch
• Thomsen, Louiza Bohn
• Heegaard, Christian Würtz
• Moos, Torben
• Burkhart, Annette

Titel

The Npc2Gt(LST105)BygNya mouse signifies pathological changes comparable to human Niemann-Pick type C2 disease

Ist Teil von

• Molecular and cellular neuroscience, 2023-09, Vol.126, p.103880-103880, Article 103880

Ort / Verlag

Elsevier Inc

Erscheinungsjahr

2023

Link zum Volltext

Quelle

Elsevier ScienceDirect Journals

Beschreibungen/Notizen

• Niemann-Pick type C2 disease (NP-C2) is a fatal neurovisceral disorder caused by defects in the lysosomal cholesterol transporter protein NPC2. Consequently, cholesterol and other lipids accumulate within the lysosomes, causing a heterogeneous spectrum of clinical manifestations. Murine models are essential for increasing the understanding of the complex pathology of NP-C2. This study, therefore, aims to describe the neurovisceral pathology in the NPC2-deficient mouse model to evaluate its correlation to human NP-C2. Npc2−/− mice holding the LST105 mutation were used in the present study (Npc2Gt(LST105)BygNya). Body and organ weight and histopathological evaluations were carried out in six and 12-week-old Npc2−/− mice, with a special emphasis on neuropathology. The Purkinje cell (PC) marker calbindin, the astrocytic marker GFAP, and the microglia marker IBA1 were included to assess PC degeneration and neuroinflammation, respectively. In addition, the pathology of the liver, lungs, and spleen was assessed using hematoxylin and eosin staining. Six weeks old pre-symptomatic Npc2−/− mice showed splenomegaly and obvious neuropathological changes, especially in the cerebellum, where initial PC loss and neuroinflammation were evident. The Npc2−/− mice developed neurological symptoms at eight weeks of age, severely progressing until the end-stage of the disease at 12 weeks. At the end-stage of the disease, Npc2−/− mice were characterized by growth retardation, tremor, cerebellar ataxia, splenomegaly, foam cell accumulation in the lungs, liver, and spleen, brain atrophy, pronounced PC degeneration, and severe neuroinflammation. The Npc2Gt(LST105)BygNya mouse model resembles the pathology seen in NP-C2 patients and denotes a valuable model for increasing the understanding of the complex disease manifestation and is relevant for testing the efficacies of new treatment strategies. •The Npc2-/- mice show neurovisceral pathology like Niemann Picks disease type C in humans and resemble the juvenile form•Neuropathological changes are evident in the cerebellum weeks before the onset of neurological symptoms•Purkinje cells show pronounced axonal swellings at the end stage of the disease•Npc2-/- mice are characterized by tremors, ataxia, Purkinje cell death, widespread neuroinflammation, and cholesterol storage