Rescue of neurodegeneration in Niemann-Pick C mice by a prion-promoter-driven Npc1 cDNA transgene

Stacie K. Loftus, Robert P. Erickson, Steven U. Walkley, Mark A. Bryant, Arturo Incao, Randall A. Heidenreich, William J. Pavan

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Niemann-Pick disease type C (NPC) is a neurodegenerative disorder with major visceral complications, including liver disease that can be fatal before onset of neurodegeneration. We have sought to determine the extent to which visceral disease contributes to neurodegeneration by making transgenic mice in which the wild-type NPC1 protein is expressed primarily in the CNS using the prion promoter. When the transgene was introduced into the npc1-/- animals neurodegeneration was prevented, a 'normal' lifespan occurred and the sterility of npc1-/- mice was corrected. The rescue did not provide complete neurological correction in the CNS as GM2 and GM3 gangliosides were observed to accumulate in some neurons and glia of transgenic animals. Two of three transgenic lines demonstrated some low-level ectopic expression resulting in correction of visceral phenotypes in liver and spleen. Interestingly, the third transgenic line continued to have moderate histocytosis in liver and spleen, yet had no detectable neurodegeneration. Thus, it is primarily the lack of NPC1 in the CNS and not the secondary effects of the visceral involvement that causes the neurological decline in NPC disease. In addition, the expression levels of NPC1 found in the CNS of transgenic animals were much greater than in normal littermates, demonstrating that overexpression of NPC1 is not harmful and allowing possibilities for genetic therapy interventions that utilize overexpression.

Original languageEnglish (US)
Pages (from-to)3107-3114
Number of pages8
JournalHuman Molecular Genetics
Volume11
Issue number24
StatePublished - Nov 15 2002

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Genetically Modified Animals
Prions
Transgenes
Spleen
Complementary DNA
G(M2) Ganglioside
Type C Niemann-Pick Disease
G(M3) Ganglioside
Genetic Engineering
Liver
Neuroglia
Neurodegenerative Diseases
Genetic Therapy
Infertility
Transgenic Mice
Liver Diseases
Phenotype
Neurons
Proteins
Ectopic Gene Expression

ASJC Scopus subject areas

  • Genetics

Cite this

Loftus, S. K., Erickson, R. P., Walkley, S. U., Bryant, M. A., Incao, A., Heidenreich, R. A., & Pavan, W. J. (2002). Rescue of neurodegeneration in Niemann-Pick C mice by a prion-promoter-driven Npc1 cDNA transgene. Human Molecular Genetics, 11(24), 3107-3114.

Rescue of neurodegeneration in Niemann-Pick C mice by a prion-promoter-driven Npc1 cDNA transgene. / Loftus, Stacie K.; Erickson, Robert P.; Walkley, Steven U.; Bryant, Mark A.; Incao, Arturo; Heidenreich, Randall A.; Pavan, William J.

In: Human Molecular Genetics, Vol. 11, No. 24, 15.11.2002, p. 3107-3114.

Research output: Contribution to journalArticle

Loftus, SK, Erickson, RP, Walkley, SU, Bryant, MA, Incao, A, Heidenreich, RA & Pavan, WJ 2002, 'Rescue of neurodegeneration in Niemann-Pick C mice by a prion-promoter-driven Npc1 cDNA transgene', Human Molecular Genetics, vol. 11, no. 24, pp. 3107-3114.
Loftus SK, Erickson RP, Walkley SU, Bryant MA, Incao A, Heidenreich RA et al. Rescue of neurodegeneration in Niemann-Pick C mice by a prion-promoter-driven Npc1 cDNA transgene. Human Molecular Genetics. 2002 Nov 15;11(24):3107-3114.
Loftus, Stacie K. ; Erickson, Robert P. ; Walkley, Steven U. ; Bryant, Mark A. ; Incao, Arturo ; Heidenreich, Randall A. ; Pavan, William J. / Rescue of neurodegeneration in Niemann-Pick C mice by a prion-promoter-driven Npc1 cDNA transgene. In: Human Molecular Genetics. 2002 ; Vol. 11, No. 24. pp. 3107-3114.
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