Petersen, R.B. et al. Familial progressive subcortical gliosis: Presence of prions and linkage to chromosome 17. Neurology 45, 1062−1067
Division of Neuropathology, Case Western Reserve University, Cleveland, OH 44106-4901, USA. Neurology
(Impact Factor: 8.29).
07/1995; 45(6):1062-7. DOI: 10.1212/WNL.45.6.1062
Progressive subcortical gliosis (PSG) is a sporadic and familial dementing disease characterized pathologically by astrogliosis at the cortex-white matter junction, a feature present in some prion diseases. With immunocytochemical and Western blot analyses, we investigated the presence of deposits of the prion protein (PrP) and of the protease-resistant PrP isoform, the hallmarks of prion diseases, in six affected members of two large kindreds with PSG. The coding region of the PrP gene was sequenced and chromosomal linkage determined. We demonstrated "diffuse" PrP plaques in the cerebral cortex of two subjects from one kindred and protease-resistant PrP fragments in four of the five subjects examined. We found no mutation in the coding region of the PrP gene. Moreover, the disease was linked to chromosome 17 and not to chromosome 20, where the PrP gene resides. The familial form of PSG is the first human genetic disease characterized by the presence of protease-resistant PrP that lacks a mutation in the coding region of the PrP gene. The linkage to chromosome 17 suggests that other genes are involved in the PrP metabolism. Whether the protease-resistant PrP plays a primary or secondary role in the pathogenesis of this form of PSG remains to be determined.
Available from: Hideyuki Okano
- "AC005325), indicating the conservation of the msi2 and msi1 genes across species, including Xenopus, mouse, and human. In human, this msi2 syntenic region contained several loci of hereditary neurological disorders: frontotemporal dementia with parkinsonism (FTDP17) (Spillantini and Geodert, 1998), Pick disease (Munoz-Garcia and Ludwin, 1984), familial progressive subcortical gliosis (GPSC) (Petersen et al., 1997), and neurofibromatosis type 1 (von Recklinghausen disease, NF1) (Mukonoweshuro et al., 1999). "
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ABSTRACT: Musashi1 (Msi1) is a mammalian neural RNA-binding protein highly enriched in neural precursor cells that are capable of generating both neurons and glia during embryonic and postnatal CNS development. Here, we identified Musashi2 (Msi2), a novel mammalian RNA-binding protein that exhibits high sequence similarity to Msi1. The Msi2 transcript appeared to be distributed ubiquitously in a wide variety of tissues, consistent with the mRNA distribution of its Xenopus homolog, xrp1. However, the present study revealed cell type-specific and developmentally regulated expression of Msi2 in the mammalian CNS. Interestingly, Msi2 was expressed prominently in precursor cells in the ventricular zone and subventricular zone with the same pattern as Msi1 throughout CNS development. In the postnatal and adult CNS, this concurrent expression of Msi2 and Msi1 was seen in cells of the astrocyte lineage, including ependymal cells, a possible source for postnatal CNS stem cells. During neurogenesis, the expression of both Msi2 and Msi1 was lost in most postmitotic neurons, whereas Msi2 expression persisted in a subset of neuronal lineage cells, such as parvalbumin-containing GABA neurons in the neocortex and neurons in several nuclei of the basal ganglia. Msi2 may have a unique role that is required for the generation and/or maintenance of specific neuronal lineages. Furthermore, in vitro studies showed that Msi2 and Msi1 have similar RNA-binding specificity. These two RNA-binding proteins may exert common functions in neural precursor cells by regulating gene expression at the post-transcriptional level.
Available from: Howard Edenberg
- "Several other familial dementias have been localized to chromosome 17q21-22. These include PPND (Wszolek et al. 1992; Yamada et al. 1993; Wijker et al. 1996), DDPAC (Lynch et al. 1994; Wilhelmsen et al. 1994; Sima et al. 1996), familial progressive subcortical gliosis (PSG) (Lanska et al. 1994; Petersen et al. 1995), and frontal lobe dementia (FLD) (Groen and Endtz 1982) and frontotemporal dementia (FLDEM) (Yamaoka et al. 1996; Heutink et al. 1997). All of these diseases, including MSTD, are autosomal dominant neurodegenerative diseases with presenile dementia. "
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ABSTRACT: An autosomal dominant presenile dementia affecting 39 individuals in a seven-generation, 383-member pedigree has been studied at Indiana University. In the affected members of this family, clinical symptoms occurred early in life, with an average age at onset of 48.8 years. The presenting clinical features include disequilibrium, neck stiffness, dysphagia, and memory loss. As the disease progresses, further cognitive decline, superior-gaze palsy, and dystaxia also are observed. The average duration from onset of symptoms to death is approximately 10 years. Neuropathologic studies of nine affected individuals showed neuronal loss in several areas of the CNS, as well as argentophilic tau-immunopositive inclusions in neurons and in oligodendroglia. A limited genomic screen by use of DNA samples from 28 family members localized the gene for this disorder to a 3-cM region on chromosome 17, between the markers THRA1 and D17S791. The gene for tau also was analyzed, through samples from the family.
Available from: Fred E Cohen
- "Although the evidence speaks to the existence of protein X, only when protein X has been identified, and either the conditions defined for its functioning in vitro or the gene encoding it ablated (thereby rendering mice resistant to prions), will protein X be shown to be distinct from PrPSc. If progressive subcortical gliosis proves to be an inherited prion disease without a PrP gene mutation, then perhaps the mutant gene responsible for this disease encodes protein X (Petersen et al., 1995). "
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ABSTRACT: Transgenic (Tg) mice expressing human (Hu) and chimeric prion protein (PrP) genes were inoculated with brain extracts from humans with inherited or sporadic prion disease to investigate the mechanism by which PrPC is transformed into PrPSc. Although Tg(HuPrP) mice expressed high levels of HuPrPC, they were resistant to human prions. They became susceptible to human prions upon ablation of the mouse (Mo) PrP gene. In contrast, mice expressing low levels of the chimeric transgene were susceptible to human prions and registered only a modest decrease in incubation times upon MoPrP gene disruption. These and other findings argue that a species-specific macromolecule, provisionally designated protein X, participates in prion formation. While the results demonstrate that PrPSc binds to PrPC in a region delimited by codons 96 to 167, they also suggest that PrPC binds protein X through residues near the C-terminus. Protein X might function as a molecular chaperone in the formation of PrPSc.
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