Gait, Balance, and Coordination Impairments in Niemann Pick Disease, Type C1

Sansare, Ashwini; Zampieri, Cris; Alter, Katharine E.; Stanley, Christopher J.; Farhat, Nicole Y.; Keener, Lee Ann; Porter, Forbes D.

doi:10.1177/0883073817741054

Cited by 2 publications

(2 citation statements)

References 34 publications

(47 reference statements)

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“…A decreased nest building activity can therefore depend on uncoordinated higher motor functions, or the motivation to organize the bedding into a nest structure for protection and warmth ( Deacon, 2006 ; Lopez et al., 2011 ). Motor skills of NPC1 −/− mice were hence analyzed next since NPC patients often present progressive functional limitations that may include difficulties with gait, balance and coordination ( Sansare et al., 2018 ). In the Rota Rod test, NPC1 −/− mice showed a progressive decrease in the latency to fall off the rod, which indicates a progressive increase of motor deficits.…”

Section: Discussionmentioning

confidence: 99%

Hepatic and neuronal phenotype of NPC1−/− mice

Santiago-Mujica¹,

Flunkert²,

Rabl

et al. 2019

Heliyon

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Niemann-Pick type C disease (NPC) is a fatal autosomal recessive disorder characterized by a defect in the intracellular transport of lipoproteins leading to the accumulation of lipids in diverse tissues. A visceral and neuronal phenotype mimicking human NPC1 disease has been described in NPC1 mutant mice. These mice are by now the most widely used NPC1 rodent model to study NPC and developmental compounds against this devastating disease. Here we characterized NPC1−/− mice for their hepatic and neuronal phenotype to confirm the stability of the phenotype, provide a characterization of disease progression and pinpoint the age of robust phenotype onset. Animals of 4–10 weeks of age were analyzed for general health, motor deficits as well as hepatic and neuronal alterations with a special focus on cerebellar pathology.Our results show that NPC1−/− mice have a reduced general health at the age of 9–10 weeks. Robust motor deficits can be observed even earlier at 8 weeks of age. Hepatic changes included increased organ weight and cholesterol levels at 6 weeks of age accompanied by severely increased liver enzyme levels. Analysis of NPC1−/− brain pathology showed decreased cholesterol and increased Aβ levels in the hippocampus at the age of 6 weeks. Further analysis revealed a decrease of the cytokine IL-12p70 in the cerebellum along with a very early increase of astrocytosis. Hippocampal IL-12p70 levels were increased at the age of 6 weeks followed by increased activated microglia levels. By the age of 10 weeks, also cerebellar Aβ levels were increased along with strongly reduced Calbindin D-28k levels.Our results validate and summarize the progressive development of the hepatic and neuronal phenotype of NPC1−/− mice that starts with cerebellar astrocytosis, making this mouse model a valuable tool for the development of new compounds against NPC.

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Section: Discussionmentioning

confidence: 99%

Hepatic and neuronal phenotype of NPC1−/− mice

Santiago-Mujica¹,

Flunkert²,

Rabl

et al. 2019

Heliyon

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“…For NPC, analysis of sphingolipids and cholesterol homeostatic responses have provided a number of proposed diagnostic plasma biomarkers such as cholesterol oxidation products (oxysterols), bile acids, (glyco)sphingolipids (GSLs) and their metabolic derivatives such as Lyso-SM509 [14][15][16][17][18][19][20]. Other biomarkers such as Bis(monoacyl)glycerophosphate (BMP), triglycerides, Calbindin, Chitotriosidase, Cathepsin D, Fatty Acid Binding Protein 3 (FABP3), Galectin 3, Heat shock protein 70 (HSP70), high/low density lipoproteins (HDL/LDL), P-Tau and amyloid-beta have been explored in various matrices such as blood, peripheral blood mononuclear cells, various organs and tissues, urine and cerebrospinal fluid (CSF) [21][22][23][24][25][26][27][28][29].…”

Section: Npc Biomarkersmentioning

confidence: 99%

Animal models for Niemann-Pick type C: implications for drug discovery & development

Fog

Kirkegaard

2019

Expert Opinion on Drug Discovery

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Introduction: Niemann-Pick type C (NPC) is a neurovisceral, progressively detrimental lysosomal storage disease with very limited therapeutic options and no approved treatment available in the US. Despite its rarity, NPC has seen increased drug developmental efforts over the past decade, culminating in the completion of two potential registration trials in 2018. Areas covered: This review highlights the many available animal models that have been developed in the field and briefly covers classical and new cell technologies. This review provides a high-level evaluation and prioritization of the various models with regard to efficient and clinically translatable drug development, and briefly discusses the relevant developments and opportunities pertaining to this. Expert opinion: With a number of in vitro and in vivo models available, and with having several drugs, all with various mechanisms of action, either approved or in late stage development, the NPC field is in an exciting time. One of the challenges for researchers and developers will be the ability to make use of the lessons learnt from existing late-stage programs as well as the incorporation not only of the opportunities but also the limitations of the many models into successful drug discovery and translational development programs.

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Gait, Balance, and Coordination Impairments in Niemann Pick Disease, Type C1

Cited by 2 publications

References 34 publications

Hepatic and neuronal phenotype of NPC1−/− mice

Hepatic and neuronal phenotype of NPC1−/− mice

Animal models for Niemann-Pick type C: implications for drug discovery & development

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