Abstract
Understanding neurodegenerative disease progression and its treatment requires the systematic characterization and manipulation of relevant cell types and molecular pathways. The neurodegenerative lysosomal storage disorder Niemann-Pick disease type C (NPC) is highly amenable to genetic approaches that allow exploration of the disease biology at the organismal, cellular and molecular level. Although NPC is a rare disease, genetic analysis of the associated neuropathology promises to provide insight into the logic of disease neural circuitry, selective neuron vulnerability and neural-glial interactions. The ability to control the disorder cell-autonomously and in naturally occurring spontaneous animal models that recapitulate many aspects of the human disease allows for an unparalleled dissection of the disease neurobiology in vivo. Here, we review progress in mouse-model-based studies of NPC disease, specifically focusing on the subtype that is caused by a deficiency in NPC1, a sterol-binding late endosomal membrane protein involved in lipid trafficking. We also discuss recent findings and future directions in NPC disease research that are pertinent to understanding the cellular and molecular mechanisms underlying neurodegeneration in general.
Highlights
Worldwide, millions of new cases of neurodegenerative disease are reported every year (Meikle et al, 1999; Van Den Eeden et al, 2003; Logroscino et al, 2008; Mayeux and Stern, 2012)
Genetics offers an excellent tool for research and, in reality, it is the rare inheritable forms of the more common age-related dementia and motor disorders – i.e. Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) – that researchers attempt to engineer animal models of and rely on for biological insight (Wong et al, 2002)
Niemann-Pick disease type C (NPC) is a rare neurodegenerative disease, the naturally occurring and engineered genetic models of the disease show great potential for the elucidation of neurodegenerative disease biology that is translatable to humans
Summary
Millions of new cases of neurodegenerative disease are reported every year (Meikle et al, 1999; Van Den Eeden et al, 2003; Logroscino et al, 2008; Mayeux and Stern, 2012). Genetics offers an excellent tool for research and, in reality, it is the rare inheritable forms of the more common age-related dementia and motor disorders – i.e. Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) – that researchers attempt to engineer animal models of and rely on for biological insight (Wong et al, 2002). These age-related diseases are predominantly idiopathic and various genetic plus environmental factors contribute to overall risk. Unlike AD, NPC and other LSDs have naturally occurring mammalian models, which can be genetically manipulated and have proven to be highly useful for testing therapies (Haskins et al, 2006; Farfel-Becker et al, 2011)
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