TY - JOUR
T1 - Transgene-driven expression of the Doppel protein in Purkinje cells causes Purkinje cell degeneration and motor impairment
AU - Anderson, Lucy
AU - Rossi, Daniela
AU - Linehan, Jackie
AU - Brandner, Sebastian
AU - Weissmann, Charles
PY - 2004/3/9
Y1 - 2004/3/9
N2 - 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 (ΔPrP) in Purkinje cells by the L7 promoter (TgL7-ΔPrP). Coexpression of full-length PrP rescued both the neurological syndromes caused by either Dpl or ΔPrP. 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-ΔPrP mice supporting the concept that Dpl and ΔPrP cause cell death, possibly by interfering with a common signaling cascade essential for cell survival.
AB - 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 (ΔPrP) in Purkinje cells by the L7 promoter (TgL7-ΔPrP). Coexpression of full-length PrP rescued both the neurological syndromes caused by either Dpl or ΔPrP. 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-ΔPrP mice supporting the concept that Dpl and ΔPrP cause cell death, possibly by interfering with a common signaling cascade essential for cell survival.
UR - http://www.scopus.com/inward/record.url?scp=1542618236&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=1542618236&partnerID=8YFLogxK
U2 - 10.1073/pnas.0308681101
DO - 10.1073/pnas.0308681101
M3 - Article
C2 - 15007176
AN - SCOPUS:1542618236
VL - 101
SP - 3644
EP - 3649
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 10
ER -