Splicing mutation of presenilin-1 gene for early-onset familial Alzheimer's disease

Sato, Shinji; Kamino, Kouzin; Miki, Tetsuro; Doi, Atsutoshi; Kunio,; George-Hyslop, Peter St; Ogihara, Toshio; Sakaki, Yoshiyuki

doi:10.1002/humu.1380110131

Cited by 40 publications

(28 citation statements)

References 14 publications

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“…PS1⌬E10 identified in FAD patients (45,46) is caused by a splice site mutation, which removes the whole sequence of exon 10 from PS1 (amino acid residue 291-319) and substitutes cysteine for serine at position 290. Therefore, the question arises whether the A␤42-promoting activity of PS1⌬E10 is acquired by the 29-amino acid deletion or by the amino acid substitution.…”

Section: Discussionmentioning

confidence: 99%

Mutational Analysis of Intrinsic Regions of Presenilin 2 That Determine Its Endoproteolytic Cleavage and Pathological Function

Shirotani¹,

Takahashi²,

Araki³

et al. 2000

Journal of Biological Chemistry

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To investigate the significance of endoproteolytic processing of presenilin 2 (PS2) on its pathological function, we constructed PS2 cDNAs causing amino acid substitutions or deletions around the cleavage site. We found that a PS2 mutant (Del3) with a 20-amino acid deletion was not endoproteolytically processed, while other PS2s with amino acid substitutions and short deletions were cleaved. Overproduction of all the mutant proteins led to a compensatory decrease of endogenous PS1 fragments, but did not affect the amyloid ␤ peptide X-42/A␤ X-40 ratio without the familial Alzheimer's disease mutation. The Del3 mutant did not exhibit significant deficits in ␥-secretase activity. The turnover rate of the Del3 holoprotein was the same as that of full-length PS2. These data suggest that the determinants of the PS2 cleavage site reside within a large region and that the pathological function of PS2 is exerted by familial Alzheimer's disease mutations not related to the cleavage of holoproteins. We also found that PS2 with an 18-amino acid deletion at the C-terminal end was not processed. Its overexpression led neither to diminished accumulation of endogenous PS1 fragments nor to increased production of amyloid ␤ peptide X-42. The Cterminal end of PS2 seems to possess the signal for entry into the processing pathway.Mutations in homologous presenilin 1 and 2 (PS1 1 and PS2) genes are associated with early-onset autosomal dominant familial Alzheimer's disease (FAD) (1-3). To date, more than 50 different pathogenic missense mutations and one splice site mutation (loss of exon 10, designated as PS1⌬E10) have been found in PS1, and two missense mutations have been identified in PS2. The gene products of PS1 and PS2 are thought to contain six or eight transmembrane (TM) domains, and the N and C termini and a large hydrophilic loop region following the sixth TM domain are located within the cytoplasm (4 -6). PS1 proteins are involved in cell fate decisions by facilitating Notch signaling pathway (7-9). Recently, PS1 proteins have been shown to have a role in the endoproteolytic processing of ␤-amyloid precursor protein (APP) (10, 11) and , and trafficking of proteins including APP (15) and Notch (12, 13), while the physiological function of PS2 proteins is poorly understood. The amount of highly amyloidogenic A␤42 (amyloid ␤ peptide 42) increases in cells and transgenic mice with the PS1 and PS2 mutant genes (16 -20), supporting a hypothesis that mutations in PS lead to Alzheimer's disease by increasing the extracellular levels of A␤42.The PS proteins are proteolytically cleaved at the hydrophilic loop region and detected predominantly as N-terminal fragments (NTF) and C-terminal fragments (CTF) in culture cells and tissues (19,(21)(22)(23). The formation of PS fragments is highly regulated in a saturable and stoichiometric manner, since overproduction of full-length PS in transfected cells and transgenic mice does not yield a linear increase of fragments (21) and causes a compensatory decrease of the endogenous PS fragments...

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Section: Discussionmentioning

confidence: 99%

Mutational Analysis of Intrinsic Regions of Presenilin 2 That Determine Its Endoproteolytic Cleavage and Pathological Function

Shirotani¹,

Takahashi²,

Araki³

et al. 2000

Journal of Biological Chemistry

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“…18 Furthermore, mutations causing splicing out of exon 9 have been identified in a Japanese and a British family. 32,33 The Japanese patients were said to represent typical AD even though it was mentioned that they had bilateral "spastic paralysis with rigidity." 32 Most of our current patients carrying a deletion of exon 9 of the PS-1 gene had spastic paraparesis, and neuropathologic analysis showed degeneration of the corticospinal tracts at the level of the pyramids and the spinal cord.…”

Section: Unusual "Cotton Wool" Plaques In the Temporal Neocortex Ofmentioning

confidence: 99%

MICAL-1 Is a Negative Regulator of MST-NDR Kinase Signaling and Apoptosis

Zhou

Adolfs

Pijnappel

et al. 2011

Molecular and Cellular Biology

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Article abstract-Objective: To present the clinical, neuroimaging, and electrophysiologic characteristics of a variant AD phenotype. Background: The authors have identified a large Finnish kindred with presenile dementia and spastic paraparesis due to deletion of exon 9 of presenilin 1. Neuropathologic analysis showed unusual cortical "cotton wool" plaques, immunoreactive for the beta-amyloid peptide but lacking congophilic cores. Patients and Methods: Twenty-two affected individuals (16 men and 6 women) were identified in four successive generations. All surviving five patients were examined and subjected to molecular genetic analysis. In addition, the neurologic records of nine deceased patients were evaluated. Electrophysiologic investigations were available in eight cases. CT or MRI of the head had been performed on 11 patients and PET was performed on three patients. Result: The mean age at onset (ϮSD) was 50.9 Ϯ 5.2 years (range 40 to 61 years). Memory impairment was present in all patients. Memory impairment appeared simultaneously with or was preceded by walking difficulty due to spasticity of the lower extremities (10/14). Impaired fine coordination of hands (9/14) and dysarthria (6/14) in some patients suggested cerebellar involvement. EEG showed intermittent generalized delta-theta activity. Head MRI showed temporal and hippocampal atrophy; PET showed bilateral temporo-parietal hypometabolism. Conclusion: Spastic paraparesis or brisk stretch reflexes of lower extremities or clumsiness of hands combined with dementia suggests this variant of AD.

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“…Two splicing defect mutations have been identified. One involves a point mutation in the splice acceptor site at the 59-end of exon 10 (in some exon numbering systems, exon 10 is labeled as exon 9) [18], and the other arises from the deletion of a G nucleotide from the splice donor site at the 39-end of exon 5 [19]. The wide scattering of missense mutations leads to the speculation that most of FAD-related mutations end up with specific functional alteration.…”

Section: Presenilin Gene Mutationsmentioning

confidence: 99%

Biomarkers of neurodegenerative disorders: How good are they?

Rachakonda

Pan

2004

Cell Res

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Biomarkers are very important indicators of normal and abnormal biological processes. Specific changes in pathologies, biochemistries and genetics can give us comprehensive information regarding the nature of any particular disease. A good biomarker should be precise and reliable, distinguishable between normal and interested disease, and differential between different diseases. It is believed that biomarkers have great potential in predicting chances for diseases, aiding in early diagnosis, and setting standards for the development of new remedies to treat diseases. New technologies have enabled scientists to identify biomarkers of several different neurodegenerative diseases. The followings, for instance, are only a few of the many new biomarkers that have been recently identified: the phosphorylated tau protein and aggregated β-amyloid peptide for Alzheimer's disease (AD), α-synuclein contained Lewy bodies and altered dopamine transporter (DAT) imaging for Parkinson's disease (PD), SOD mutations for familial amyotrophic lateral sclerosis (ALS), and CAG repeats resulted from Huntington's gene mutations in Huntington's disease (HD). This article will focus on the most-recent findings of biomarkers belonging to the four mentioned neurodegenerative diseases.

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Splicing mutation of presenilin-1 gene for early-onset familial Alzheimer's disease

Cited by 40 publications

References 14 publications

Mutational Analysis of Intrinsic Regions of Presenilin 2 That Determine Its Endoproteolytic Cleavage and Pathological Function

Mutational Analysis of Intrinsic Regions of Presenilin 2 That Determine Its Endoproteolytic Cleavage and Pathological Function

MICAL-1 Is a Negative Regulator of MST-NDR Kinase Signaling and Apoptosis

Biomarkers of neurodegenerative disorders: How good are they?

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