An important part of neural development involves setting up and refining the architecture and function of dendrites, the "receiving ends" of nerve cells that communicate with their partners in circuits. The biological processes involved in building and maintaining dendrites require high levels of metabolic activity that need to be turned on and off repeatedly in a spatially and temporally restricted way. The metabolic processes that synthesize (anabolism) and break down (catabolism) complex molecules involved in dendrite building and remodeling are not completely understood. This project examines the interplay between anabolic and catabolic pathways during the formation of Purkinje cell dendrites (which have some of the largest dendritic trees in the brain) within the mouse cerebellum.

NSF Award Number 2243243. Directorate for Biological Sciences, Division Of Integrative Organismal Systems.

Niemann-Pick type C (NPC) is a lysosomal storage disease that is inherited in an autosomal recessive manner. Mutations in Npc1, a protein that exports cholesterol out of the lysosomes, cause the abnormal accumulation of cholesterol in lysosomes, a hallmark of NPC. Neurological symptoms of NPC include ataxia, cognitive impairment, and dementia that lead to premature death. Purkinje cells (PCs) are among the most susceptible neurons to Npc1 deficiency, leading to their early degeneration and the development of early neurological symptoms such as clumsiness, gait defects, and ataxia. Studies in our laboratory and by others have shown that microglia reactivity and increased phagocytic responses occur early, before the degeneration of Purkinje cells, and contribute to the loss of these cells in the cerebellum. Given that neurological symptoms result from severe neurodegeneration, a major goal of this project is to understand how NPC1 deficiency affects microglia and Purkinje cells during postnatal development, an asymptomatic stage in childhood NPC that precedes Purkinje cell degeneration.

This project is funded by the National Institute of Neurological Disorders and Stroke, 2R15NS104994-02.