Niemann Pick Type C Disease as a Model for Defects in Neurosteroidogenesis

Abstract

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 ∼ embryonic day 7. Cyp17 was expressed in the embryonic endoderm at E7, where 17α hydroxylase and c17,20 lyase activities were found. Hormonal replacement was ineffective in rescuing the embryos. The function of P450c17 and/or its steroid products in early mouse development is unknown. In the second model, we used a naturally‐occurring NP‐C mutant mouse. Mutations in the npc1 gene results in lysosomal accumulation of cholesterol and gangliosides in humans and in the mouse, which also recapitulates the onset of neurological deficits, neuronal loss and death typical of the most severe form of the human disease. We showed that there is a substantial reduction in the synthesis of the neurosteroid allopregnanolone (ALLO) at birth, which may lead to abnormal neural development. ALLO treatment was highly effective; ALLO‐treated NP‐C mice had substantially increased survival and delays in neurologic impairments, coinciding with marked improvements in neuronal survival, and reduction of gangliosides. These data suggest that neurosteroids play an important role in brain development and maturation and may be an effective therapy for NP‐C and perhaps other lysosomal storage diseases.

Acknowledgments

This work was supported by grants from the NIH (HD27970), NSF (0090905), The Ara Parseghian Medical Research Foundation, The National Niemann Pick Disease Foundation, and The March of Dimes.