Transgene-driven expression of the Doppel protein in Purkinje cells causes Purkinje cell degeneration and motor impairment.
The Doppel (Dpl) and Prion (PrP) proteins show 25% sequence identity and share several structural features with only minor differences. Dpl shows a PrP-like fold of its C-terminal globular domain and lacks the flexible N-terminal tail. The physiological functions of both proteins are unknown. However, ubiquitous Dpl overexpression in the brain of PrP knockout mice correlated with ataxia and Purkinje cell degeneration in the cerebellum. Interestingly, a similar phenotype was reported in transgenic mice expressing an N-terminally truncated PrP (DeltaPrP) in Purkinje cells by the L7 promoter (TgL7-DeltaPrP). Coexpression of full-length PrP rescued both the neurological syndromes caused by either Dpl or DeltaPrP. To evaluate whether the two proteins caused cerebellar neurodegeneration by the same mechanism, we generated transgenic mice selectively expressing Dpl in Purkinje cells by the same L7 promoter. Such mice showed ataxia and Purkinje cell loss that depended on the level of Dpl expression. Interestingly, the effects of high levels of Dpl were not counterbalanced by the presence of two Prnp alleles. By contrast, PrP coexpression was sufficient to abrogate motor impairment and to delay the neurodegenerative process caused by moderate level of Dpl. A similar situation was reported for the corresponding TgL7-DeltaPrP mice supporting the concept that Dpl and DeltaPrP cause cell death, possibly by interfering with a common signaling cascade essential for cell survival.
Medical Research Council Prion Unit and Department of Neurodegenerative Disease, and Division of Neuropathology, Institute of Neurology, University College, Queen Square, London WC1N 3BG, United Kingdom.
Lucy
L
Anderson
Daniela
D
Rossi
Jackie
J
Linehan
Sebastian
S
Brandner
Charles
C
Weissmann
D000818:Animals; D001483:Base Sequence; D002524:Cerebellar Ataxia / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018076:DNA, Complementary / Q000235:genetics; D058851:GPI-Linked Proteins; D005816:Genetic Complementation Test; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011328:Prions / Q000235:genetics* / Q000378:metabolism*; D011689:Purkinje Cells / Q000378:metabolism* / Q000473:pathology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D018076:DNA, Complementary; D058851:GPI-Linked Proteins; D011328:Prions; C122036:Prnd protein, mouse; D011994:Recombinant Proteins