Familial Alzheimer's chromosome 14 mutations

Wasco, Wilma; Wp, Pettingell; Pd, Jondro; Sd, Schmidt; Gurubhagavatula, Sarada; Rodes, Linda; Di-Blasi, Tatiana; Dm, Romano; Sy, Guenette; Dm, Kovacs

doi:10.1038/nm0995-848a

Cited by 103 publications

(50 citation statements)

References 2 publications

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“…On the other hand, familial early onset Alzheimer's disease is caused by point mutations in the amyloid precursor protein gene on chromosome 21 (8), in the presenilin 2 (PS2) 1 gene on chromosome 1 (9 -11), or, most frequently, in the presenilin 1 (PS1) gene on chromosome 14 (12)(13)(14)(15). Amyloid precursor protein (APP) is a type I integral membrane protein and is the precursor of the amyloid peptide, the main component of the senile plaques (1)(2)(3).…”

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confidence: 99%

Phosphorylation, Subcellular Localization, and Membrane Orientation of the Alzheimer's Disease-associated Presenilins

Strooper¹,

Beullens²,

Contreras

et al. 1997

Journal of Biological Chemistry

272

187

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Presenilins 1 and 2 are unglycosylated proteins with apparent molecular mass of 45 and 50 kDa, respectively, in transfected COS-1 and Chinese hamster ovary cells. They colocalize with proteins from the endoplasmic reticulum and the Golgi apparatus in transfected and untransfected cells. In COS-1 cells low amounts of intact endogeneous presenilin 1 migrating at 45 kDa are detected together with relative larger amounts of presenilin 1 fragments migrating between 18 and 30 kDa. The presenilins have a strong tendency to form aggregates (mass of 100 -250 kDa) in SDS-polyacrylamide gel electrophoresis, which can be partially resolved when denatured by SDS at 37°C instead of 95°C. Sulfation, glycosaminoglycan modification, or acylation of the presenilins was not observed, but both proteins are posttranslationally phosphorylated on serine residues. The mutations Ala-246 3 Glu or Cys-410 3 Tyr that cause Alzheimer's disease do not interfere with the biosynthesis or phosphorylation of presenilin 1. Finally, using low concentrations of digitonin to selectively permeabilize the cell membrane but not the endoplasmic reticulum membrane, it is demonstrated that the two major hydrophilic domains of presenilin 1 are oriented to the cytoplasm. The current investigation documents the posttranslational modifications and subcellular localization of the presenilins and indicates that postulated interactions with amyloid precursor protein metabolism should occur in the early compartments of the biosynthetic pathway.

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confidence: 99%

Phosphorylation, Subcellular Localization, and Membrane Orientation of the Alzheimer's Disease-associated Presenilins

Strooper¹,

Beullens²,

Contreras

et al. 1997

Journal of Biological Chemistry

272

187

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“…Rather, most FAD cases appear to be caused by mutations in the recently identified PS1 and PS2 genes (8,9). PS1 encodes a novel protein of 467 amino acids that contains seven potential transmembrane domains (8), and at least 24 different missense mutations in PS1 have been identified that cosegregate with the AD phenotype in multiple FAD pedigrees (8,(10)(11)(12)(13)(14)(15). PS2 is >70% homologous to PS1 and is predicted to encode a protein of 448 amino acids with a topology identical to that of PS1 (9).…”

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confidence: 99%

Expression and analysis of presenilin 1 in a human neuronal system: localization in cell bodies and dendrites.

Cook

Sung

Golde

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

200

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Mutations in the recently identified presenilin 1 gene on chromosome 14 cause early onset familial Alzheimer disease (FAD). Herein we describe the expression and analysis of the protein coded by presenilin 1 (PS1) in NT2N neurons, a human neuronal model system. PS1 was expressed using recombinant Semliki Forest virions and detected by introduced antigenic tags or antisera to PS1-derived peptides. Immunoprecipitation revealed two major PS1 bands of approximately 43 and 50 kDa, neither of which were N-glycosylated or 0-glycosylated. Immunoreactive PS1 was detected in cell bodies and dendrites of NT2N neurons but not in axons or on the cell surface. PS1 was also detected in BHK cells, where it was also intracellular and colocalized with calnexin, a marker for the rough endoplasmic reticulum. A mutant form of PS1 linked to FAD did not differ from the wild-type protein at the light microscopic level. The model system described here will enable studies of the function of PS1 in human neurons and the role of mutant PS1 in FAD.Since mutations in the PS1 and PS2 genes result in early onset FAD that is quite similar to FAD in other pedigrees with APP mutations, the PS mutations may cause AD by altering the metabolism of APP and/or AP3, thereby accelerating amyloidogenesis. Considerable evidence suggests that neurons are a major source of the AP3 that forms amyloid deposits in AD (17, 18), and a recent study showed that within the brain PS1 and PS2 mRNAs are expressed primarily in neurons (19). For these reasons, it is important to study the biosynthesis and processing of these genes in neurons. To accomplish this goal, we developed a strategy to efficiently express and detect PS1 in a well characterized in vitro model of human neurons (NT2N cells) (20). We found that PS1 was localized in the cell body and dendrites of NT2N neurons but not on the cell surface or in axons.

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“…The majority of early onset familial AD appears to be due to mutations in two recently discovered genes, presenilin 1 (PS-1) located on chromosome 14 (4), which is responsible for AD in multiple pedigrees, and PS-2, located on chromosome 1, which is responsible for AD in the well studied Volga German families (5,6). Twenty-four mutations have already been discovered in PS-1 in 52 pedigrees, and two mutations in PS-2 have been described (4)(5)(6)(7)(8)(9)(10)(11)(12)(13). PS-1 and PS-2 are 67% identical to one another, and also share marked homology of approximately 50% identity with the Caenorhabditis elegans gene product Sel-12.…”

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confidence: 99%

In situ hybridization analysis of presenilin 1 mRNA in Alzheimer disease and in lesioned rat brain

Page

Hollister

Tanzi

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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Presenilin-1 (PS-1) gene mutations are responsible for the majority of the early onset familial forms of Alzheimer disease (AD). Neither PS-1's anatomic distribution in brain nor expression in AD have been reported. Using in situ hybridization in the rat forebrain, we show that PS-1 mRNA expression is primarily in cortical and hippocampal neurons, with less expression in subcortical structures, in a regional pattern similar to APP695. Excitotoxic lesions lead to loss of PS-1 signal. A neuronal pattern of expression of PS-1 mRNA was also observed in the human hippocampal formation. AD and control levels did not differ. PS-1 is expressed in brain areas vulnerable to AD changes more so than in areas spared in AD; however, PS-1 expression is not sufficient to mark vulnerable regions. Collectively, these data suggest that the neuropathogenic process consequent to PS-1 mutations begins in neuronal cell populations.Alzheimer disease (AD) is a widespread and devastating neurodegenerative disorder that manifests itself as a progressive and irreversible decline in cognitive abilities associated with the development of neurofibrillary tangles and senile plaques in a distinctive pattern in the brain. The underlying causes and pathophysiologic mechanisms of AD remain unknown. Molecular analysis in recent years has suggested that the causes may be heterogeneous. There are now four well established genes associated with AD. Inheritance of a common allele of the apolipoprotein E gene, apoE 4, is a risk factor for late onset (Ͼ60 years old) AD (1). The other three genes are causative and lead to autosomal dominant forms of the disease with fairly early ages of onset (Ͻ60 years, frequently even in the 40s). Mutations in the amyloid precursor protein (APP) (2) account for a small percentage of early onset familial AD cases (3). The majority of early onset familial AD appears to be due to mutations in two recently discovered genes, presenilin 1 (PS-1) located on chromosome 14 (4), which is responsible for AD in multiple pedigrees, and PS-2, located on chromosome 1, which is responsible for AD in the well studied Volga German families (5, 6). Twenty-four mutations have already been discovered in PS-1 in 52 pedigrees, and two mutations in PS-2 have been described (4-13). PS-1 and PS-2 are 67% identical to one another, and also share marked homology of approximately 50% identity with the Caenorhabditis elegans gene product . The predicted amino acid sequence of PS-1 suggests a protein structure that is serpentine, with multiple hydrophilic loops separated by transmembrane domains.The normal role of the PS-1 gene product is unknown, and its role in the pathophysiology of AD remains speculative. PS-1 mRNA is ubiquitously expressed, but detailed knowledge of its expression and localization in the brain is not yet available. Our initial studies suggest a neuronal localization in normal human brain (15). We have now used oligonucleotide probes to examine AD and control brain expression of PS-1 mRNA. In addition, a mouse homologue o...

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Familial Alzheimer's chromosome 14 mutations

Cited by 103 publications

References 2 publications

Phosphorylation, Subcellular Localization, and Membrane Orientation of the Alzheimer's Disease-associated Presenilins

Phosphorylation, Subcellular Localization, and Membrane Orientation of the Alzheimer's Disease-associated Presenilins

Expression and analysis of presenilin 1 in a human neuronal system: localization in cell bodies and dendrites.

In situ hybridization analysis of presenilin 1 mRNA in Alzheimer disease and in lesioned rat brain

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