Genetic dissection of a cell-autonomous neurodegenerative disorder: lessons learned from mouse models of Niemann-Pick disease type C

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.

Hepatic Primary and Secondary Cholesterol Deposition and Damage in Niemann-Pick Disease

“…The current view is that hepatic and neuronal diseases progress independently in NP-C. 4 A mouse with specific loss of neuronal NPC1 recapitulates the neurodegeneration of the NPC1-null animal. 5,6 However, although specific neuronal NPC1 re-expression in NPC1-null mice increases survival, neurologic defects still are observed.…”

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

“…The NPC1 gene is highly conserved among eukaryotes, making it possible to generate NPC models ranging from mammals to fungi, including cat, mouse, zebrafish, fruit fly, nematode and yeast models of NPC [36] (Table 1). In addition to the aforementioned model organisms, neuronal cells differentiated from stem cells or other sources of human or murine origin have successfully been used as orthogonal model systems for drug screening and testing [37].…”

Modeling Niemann Pick type C1 using human embryonic and induced pluripotent stem cells

“…For these reasons and due to advantages attributable to scale, the naturally occurring cat model of NPC1 may be better suited to test proposed therapies for NPC1 (Brown et al, 1994; Somers et al, 2003). Although these animal models are important tools for understanding the disease biology and for in vivo therapeutic development, the use of animal models is prohibitively expensive and frequently inadequate for high throughput drug discovery programs (Lopez and Scott, 2013). …”

“…glia) to disease pathogenesis. Whereas it is generally well established that neuronal failure in NPC1 is a cell autonomous event (Ko et al, 2005; Lopez and Scott, 2013), it is possible that mutations of NPC1 in glia may disrupt cholesterol trafficking between glial and neuronal cells (Erickson, 2013). Experiments designed to address this question have thus far used co-culturing of NPC1 mouse neurons with wild type glia that do not share the same genetic background.…”