Biological effects of four PSEN1 gene mutations causing Alzheimer disease with spastic paraparesis and cotton wool plaques (original) (raw)
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Brain, 2003
Several pedigrees have recently been reported in which dominantly inherited familial Alzheimer's disease is associated in some family members with spastic paraparesis and non-neuritic`cotton wool' plaques. Here we report clinical, genetic and neuropathological ®ndings in two further large pedigrees in which this combination of phenotypes is associated with a deletion of exon 9 of the presenilin-1 (PS-1) gene caused by mutations at the splice acceptor site. In both pedigrees, indi-viduals with paraparesis at presentation had a later than average age at onset of symptoms. In addition, one subject with paraparesis had a much less prominent dementia syndrome than his dementia-affected siblings. As PS-1 mutations are almost always associated with a particularly aggressive form of presenile dementia, these ®ndings suggest the existence of a protective or delaying factor in individuals with spastic paraparesis.
Annals of Neurology, 2000
Fatal familial insomnia (FFI) is a unique hereditary prion disease with characteristic disturbances of sleep. We studied the serotonergic system in 8 FFI-affected subjects by immunohistochemistry for the serotonin-synthesizing enzyme, tryptophan hydroxylase (TH). Quantification of neurons in median raphe nuclei showed no total neuronal loss in FFI but a substantial increase of TH ؉ neurons (ϳ62%) in FFI subjects compared with controls. Our data indicate an alteration of the serotonergic system that might represent the functional substrate of some typical symptoms of FFI. Wanschitz J, Klöppel S, Jarius C, Birner P, Flicker H, Hainfellner JA, Gambetti P, Guentchev M, Budka H. Alteration of the serotonergic nervous system in fatal familial insomnia. Ann Neurol 2000;48:788 -791
Journal of Biological Chemistry, 2002
The mutation L271V in exon 8 of the presenilin-1 (PS-1) gene was detected in an Alzheimer's disease pedigree. Neuropathological examination of affected individuals identified variant, large, non-cored plaques without neuritic dystrophy, reminiscent of cotton wool plaques. Biochemical analysis of L271V mutation showed that it increased secretion of the 42-amino acid amyloid- peptide, suggesting a pathogenic mutation. Analysis of PS-1 transcripts from the brains of two mutation carriers revealed a 17-50% increase in PS-1 transcripts with deletion of exon 8 (PS-1⌬exon8) compared with unrelated Alzheimer's disease brains. Exon trapping analysis confirmed that L271V mutation enhanced the deletion of exon 8. Western blots of brain lysates indicated that PS-1⌬exon8 was overexpressed in an affected individual. Biochemical analysis of PS-1⌬exon8 in COS and BD8 cells indicate the splice isoform is not intrinsically active but interacts with wild-type PS-1 to generate amyloid-. Western blots of cell lysates immunoprecipitated with anti-Tau or anti-GSK-3 antibodies indicated that PS-1⌬exon8, unlike wild-type PS-1, does not interact directly with Tau or GSK-3, potential modifiers of neuritic dystrophy. We postulate that variant plaques observed in this family are due in part to the effects of PS-1⌬exon8 and that interaction between PS-1 and various protein complexes are necessary for neuritic plaque formation.
Journal of Alzheimer's disease : JAD, 2011
We report a novel presenilin1 (PSEN1) gene mutation (I143 V) in a four-generation family with Alzheimer's disease. Clinical, molecular, and neuropathological examinations were performed on index patient; thirteen affected subjects were also identified. The index patient presented at 55 with personality changes, apathy, reduction of verbal fluency, and temporal and spatial disorientation. At 68, she showed visual hallucinations; blurred language, and rigidity. She became bedridden and died at 75. A novel mutation at codon 143 was found in PSEN1 gene, changing isoleucine to valine. The brain showed severe atrophy of the frontal and temporal lobes. Parenchymal amyloid-β (Aβ) deposits were abundant, diffuse to grey structures and contained Aβ42, but very few Aβ40. Amyloid angiopathy was absent. Neurofibrillary changes were severe. Our study confirms that PSEN1 mutations can be associated with unusual phenotypes. The peculiarity of the age at onset (not very early), the long course, ...
Alternative splicing in a presenilin 2 variant associated with Alzheimer disease
Annals of clinical and translational neurology, 2019
Objective: Autosomal-dominant familial Alzheimer disease (AD) is caused by by variants in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP). Previously, we reported a rare PSEN2 frameshift variant in an early-onset AD case (PSEN2 p.K115Efs*11). In this study, we characterize a second family with the same variant and analyze cellular transcripts from both patient fibroblasts and brain lysates. Methods: We combined genomic, neuropathological, clinical, and molecular techniques to characterize the PSEN2 K115Efs*11 variant in two families. Results: Neuropathological and clinical evaluation confirmed the AD diagnosis in two individuals carrying the PSEN2 K115Efs*11 variant. A truncated transcript from the variant allele is detectable in patient fibroblasts while levels of wild-type PSEN2 transcript and protein are reduced compared to controls. Functional studies to assess biological consequences of the variant demonstrated that PSEN2 K115Efs*11 fibroblasts secrete less Ab 1-40 compared to controls, indicating abnormal c-secretase activity. Analysis of PSEN2 transcript levels in brain tissue revealed alternatively spliced PSEN2 products in patient brain as well as in sporadic AD and age-matched control brain. Interpretation: These data suggest that PSEN2 K115Efs*11 is a likely pathogenic variant associated with AD. We uncovered novel PSEN2 alternative transcripts in addition to previously reported PSEN2 splice isoforms associated with sporadic AD. In the context of a frameshift, these alternative transcripts return to the canonical reading frame with potential to generate 762
Genomics, 1997
the presenilin I gene (S182 or PSEN1) on chromosome Mutations in the human presenilin genes (PSEN1 and 14q24.3 and in the homolo-PSEN2) are associated with early onset familial Alzheigous gene presenilin II (E5-1 or PSEN2) on chromomer disease. The presenilin genes encode integral memsome 1 . brane proteins with similar structures, which suggests The proteins encoded by the mammalian presenilin that they may have closely related, but as yet unknown genes are predicted to be multispanning membrane functions. Analysis of the 5 upstream sequence and the proteins predominantly located in the endoplasmic restructure of the PSEN1 gene reveals that the 5 sequence ticulum, Golgi, and an as yet uncharacterized intracycontains multiple putative transcription regulatory eletoplasmic vesicular structure (Levesque et al., submitments including clusters of STAT elements involved in ted for publication). The function of the mammalian transcriptional activation in response to signal transpresenilin proteins is unknown. However, a Caenoduction. The first four exons contain untranslated serhabditis elegans orthologue, sel-12, affects lin-12/ quences, with Exons 1 and 2 representing alternate ininotch-mediated intercellular signaling pathways (Levitial transcription sites. The function of these alternate tan and . A second C. elegans gene, initial exons is unclear. Exon 4 bears the first ATG se-spe4, shows weaker similarities to the mammalian prequence. The last 12 bp of Exon 4 is used as an alternative senilins and is expressed in a Golgi-derived membranesplice donor site. Exon 9 is alternately spliced in leukobound organelle in C. elegans spermatocytes, where it cytes, but not in most other tissues. Splicing of Exon 9 is thought to be involved in membrane/protein traffickis predicted to cause significant structural changes to ing (L'Hernault and Arduengo, 1992).
International Journal of Molecular Sciences, 2021
Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder caused by the deposition of amyloid beta-peptide (Aβ) aggregates. Aβ aggregates lead to vessel rupture and intracerebral hemorrhages, detected by magnetic resonance imaging (MRI). Presenile CAA is usually genetically determined by mutations in the amyloid precursor protein (APP) gene. However, mutations after codon 200 in the presenilin 1 (PSEN1) gene have been reported to facilitate CAA onset. Here, we analyzed the genetic bases in a patient of 55 years old affected by CAA and cognitive decline. DNA was isolated and genetic analysis was performed by Next-Generation Sequencing (NGS). RNA was extracted and retro-transcribed to perform segregation analysis by TOPO-TA cloning. WB analysis was carried out to check the impact of the mutations on protein. Two compound heterozygous mutations in PSEN1 exon 10, such as a novel stop-gain mutation (c.1070C > G) and a pathogenic splice variant (c.1129A > T), were found by NGS...
European Journal of Neurology, 2007
The aim of this study was to describe a novel mutation in exon 8 of the presenilin gene (L286P) associated with early-onset autosomal dominant Alzheimer's disease (AD) and lobar haematomas. The proband was a woman who developed cognitive decline with predominant memory loss at the age of 35 years. The patient died at the age of 54 years and the neuropathological examination confirmed the diagnosis of AD. Three of her four siblings, one parent and one sibling of her parent had suffered from cognitive decline at ages between 35 and 42 years. Three of them also presented lobar haematomas. The neuropathological examination, available in one of them, disclosed the presence of severe amyloid angiopathy as the cause of the haematoma. The study of PSEN1 gene with single strand conformation polymorphism technique failed to show abnormalities suggestive of mutations. Direct sequencing disclosed the presence of a missense mutation in codon 286 (L286P) in the proband and her already affected descendent, which was absent in the healthy sibling. L286P is a novel mutation in PSEN1 that causes familial early-onset AD and brain haematomas related to amyloid angiopathy.
Exploring the Role of PSEN Mutations in the Pathogenesis of Alzheimer’s Disease
Neurotoxicity Research, 2020
Alzheimer's disease (AD) is the most common cause of dementia. Mutations of presenilin (PSEN) genes that encode presenilin proteins have been found as the vital causal factors for early-onset familial AD (FAD). AD pathological features such as memory loss, synaptic dysfunction, and formation of plaques have been successfully mimicked in the transgenic mouse models that coexpress FAD-related presenilin and amyloid precursor protein (APP) variants. γ-Secretase (GS) is an enzyme that plays roles in catalyzing intramembranous APP proteolysis to release pathogenic amyloid beta (Aβ). It has been found that presenilins can play a role as the GS's catalytic subunit. FAD-related mutations in presenilins can modify the site of GS cleavage in a way that can elevate the production of longer and highly fibrillogenic Aβ. Presenilins can interact with β-catenin to generate presenilin complexes. Aforesaid interactions have also been studied to observe the mutational and physiological activities in the catenin signal transduction pathway. Along with APP, GS can catalyze intramembrane proteolysis of various substrates that play a vital role in synaptic function. PSEN mutations can cause FAD with autosomal dominant inheritance and early onset of the disease. In this article, we have reviewed the current progress in the analysis of PSENs and the correlation of PSEN mutations and AD pathogenesis.
Neurobiology of disease, 2017
Presenilin 1 (PSEN1) mutations are the main cause of autosomal dominant Early-onset Alzheimer Disease (EOAD). Among them, deletions of exon 9 have been reported to be associated with a phenotype of spastic paraparesis. Using exome data from a large sample of 522 EOAD cases and 584 controls to search for genomic copy-number variations (CNVs), we report here a novel partial, in-frame deletion of PSEN1, removing both exons 9 and 10. The patient presented with memory impairment associated with spastic paraparesis, both starting from the age of 56years. He presented a positive family history of EOAD. We performed functional analysis to elucidate the impact of this novel deletion on PSEN1 activity as part of the γ-secretase complex. The deletion does not affect the assembly of a mature protease complex but has an extreme impact on its global endopeptidase activity. The mutant carboxypeptidase-like activity is also strongly impaired and the deleterious mutant effect leads to an incomplete ...