Niemann pick type C disease as a model for defects in neurosteroidogenesis.

Many functions have been attributed to neurosteroids including actions as anxiolytics, roles in myelination, inhibitors of neuronal toxicity and ischemia, and roles in neuronal growth and differentiation. To understand the functions of neurosteroids during nervous system development, we used two mouse models: one, in which the cyp17 gene was ablated, thus ablating synthesis of the neurosteroid DHEA, and a second, in a mouse model of a human childhood fatal neurodegenerative disease, Niemann-Pick Type C (NP-C). Cyp17-/- mice died unexpectedly approximately embryonic day 7.

Niemann-Pick type C disease involves disrupted neurosteroidogenesis and responds to allopregnanolone.

Niemann-Pick type C (NP-C) disease is a fatal, autosomal recessive, childhood neurodegenerative disease. The NP-C mouse recapitulates the cholesterol and sphingolipid storage, onset of neurological deficits, histopathological lesions, Purkinje cell loss and early death typical of the most severe form of human NP-C. Neurosteroids, steroids made in the brain, affect neuronal growth and differentiation, and modulate neurotransmitter receptors.

Neurosteroids: biochemistry and clinical significance.

The brain, like the adrenals, gonads and the placenta, is a steroidogenic tissue. However, unlike classic steroidogenic tissues, the synthesis of steroids in the nervous system requires coordinated expression and regulation of genes encoding the steroidogenic enzymes in several different cell types (neurons and glia) at different locations in the nervous system, often at some distance from the cell bodies. Furthermore, the synthesis of these steroids might be developmentally regulated and related to their functions in the developing brain.