title: Deletion of N-terminal residues 23-88 from prion protein (PrP) abrogates the potential to rescue PrP-deficient mice from PrP-like protein/doppel-induced Neurodegeneration.
abstract: Accumulating evidence has suggested that prion protein (PrP) is neuroprotective and that a PrP-like protein/Doppel (PrPLP/Dpl) is neurotoxic. A line of PrP-deficient mice, Ngsk Prnp0/0, ectopically expressing PrPLP/Dpl in neurons, exhibits late-onset ataxia because of Purkinje cell death that is prevented by a transgene encoding wild-type mouse PrP. To elucidate the mechanisms of neurodegeneration in these mice, we introduced five types of PrP transgene, namely one heterologous hamster, two mouse/hamster chimeric genes, and two mutants, each of which encoded PrP lacking residues 23-88 (MHM2.del23-88) or with E199K substitution (Mo.E199K), into Ngsk Prnp0/0 mice. Only MHM2.del23-88 failed to rescue the mice from the Purkinje cell death. The transgenic mice, MHM2.del23-88/Ngsk Prnp0/0, expressed several times more PrP than did wild-type (Prnp+/+) mice and PrPLP/Dpl at an equivalent level to Ngsk Prnp0/0 mice. Little difference was observed in the pathology and onset of ataxia between Ngsk Prnp0/0 and MHM2.del23-88/Ngsk Prnp0/0. No detergent-insoluble PrPLP/Dpl was detectable in the central nervous system of Ngsk Prnp0/0 mice even after the onset of ataxia. Our findings provide evidence that the N-terminal residues 23-88 of PrP containing the unique octapeptide-repeat region is crucial for preventing Purkinje cell death in Prnp0/0 mice expressing PrPLP/Dpl in the neuron.
authors.affiliation: Department of Molecular Microbiology and Immunology, Institute of Atomic Bomb Disease, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Atarashi
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Nishida
authors.forename: Kazuto
authors.initials: K
authors.lastname: Shigematsu
authors.forename: Shinji
authors.initials: S
authors.lastname: Goto
authors.forename: Takahito
authors.initials: T
authors.lastname: Kondo
authors.forename: Suehiro
authors.initials: S
authors.lastname: Sakaguchi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Katamine
mesh_terms: D000818:Animals; D001259:Ataxia / Q000235:genetics / Q000473:pathology; D001921:Brain / Q000201:enzymology / Q000473:pathology; D064026:Calbindins; D016923:Cell Death / Q000235:genetics; D006224:Cricetinae; D003902:Detergents; D058851:GPI-Linked Proteins; D017353:Gene Deletion; D015870:Gene Expression; D005979:Glutathione Peroxidase / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D010641:Phenotype; D011257:Pregnancy Proteins / Q000737:chemistry* / Q000172:deficiency* / Q000235:genetics; D011328:Prions / Q000235:genetics*; D011689:Purkinje Cells / Q000473:pathology; D012091:Repetitive Sequences, Nucleic Acid; D064030:S100 Calcium Binding Protein G / Q000032:analysis; D012995:Solubility; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D064026:Calbindins; D003902:Detergents; D058851:GPI-Linked Proteins; D010446:Peptide Fragments; C057074:Plfr protein, mouse; D011257:Pregnancy Proteins; D011328:Prions; C122036:Prnd protein, mouse; D064030:S100 Calcium Binding Protein G; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase