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

Nature Medicine volume 10, pages 704–711 (2004)Cite this article

Abstract

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. Disordered cholesterol trafficking might disrupt neurosteroidogenesis, thereby contributing to the NP-C phenotype. Here we show that NP-C mouse brain contains substantially less neurosteroid than wild-type brain and has an age-related decrease in the ability to synthesize 5α-dihydroprogesterone and allopregnanolone. Immunohistochemical assessment confirms a decrease in expression of 5α-reductase and 3α-hydroxysteroid dehydrogenase, especially in cerebellum. Neonatal administration of allopregnanolone delays the onset of neurological symptoms, increases Purkinje and granule cell survival, reduces cortical GM2 and GM3 ganglioside accumulation and doubles the lifespan of NP-C mice. Earlier administration increases effectiveness of treatment. Decreased production of allopregnanolone apparently contributes to the pathology of NP-C; thus, neurosteroid treatment may be useful in ameliorating progression of the disease.

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Figure 1: Neurosteroidogenesis in wild-type and NP-C mice.
Figure 2: Cortical and cerebellar neurosteroidogenic enzyme expression in wild-type and NP-C mice.
Figure 3: Role of GABAA receptors in mediating response to allopregnanolone.
Figure 4: Effect of allopregnanolone (Allo) injections on progression of NP-C symptoms.
Figure 5: Cerebellar histology in NP-C mice treated with allopregnanolone at P7.
Figure 6: Ganglioside profiles in cortex from NP-C mice treated with allopregnanolone.

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Acknowledgements

We thank C. Brown, T. Tang and P. Hoang for technical assistance; B. Robaire for antiserum to rat 5α-reductase type 1; W.L. Miller for antiserum to human P450scc; J.I. Mason for antiserum to human 3βHSD; P. Sluss for antiserum to allopregnanolone; and M.T. Vanier, in whose laboratory the lipid analyses were done. This work was supported by the National Institutes of Health (S.H.M. and L.D.G.), National Niemann Pick Disease Foundation (S.H.M. and L.D.G.), March of Dimes Birth Defects Foundation (S.H.M.), Ara Parseghian Medical Research Foundation (S.H.M.) and Vaincre les Maladies Lysosomales (L.V.).

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Author notes

  1. Lisa D Griffin and Wenhui Gong: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Gynecology & Reproductive Sciences and the Center for Reproductive Sciences, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, 94143-0556, California, USA

    Lisa D Griffin

  2. Department of Obstetrics, Gynecology & Reproductive Sciences and the Center for Reproductive Sciences, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, 94143-0556, California, USA

    Wenhui Gong & Synthia H Mellon

  3. INSERM U189 and Laboratoire Fondation Gillet-Merieux, Lyon-Sud Medical School and Hospital, Pierre-Benite, 69310, France

    Lucie Verot

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Correspondence to Synthia H Mellon.

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Griffin, L., Gong, W., Verot, L. et al. Niemann–Pick type C disease involves disrupted neurosteroidogenesis and responds to allopregnanolone. Nat Med 10, 704–711 (2004). https://doi.org/10.1038/nm1073

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