Three novel presenilin 1 mutations marking the wide spectrum of age at onset and clinical patterns in familial Alzheimer’s disease

Roeber, Sigrun; Müller‐Sarnowski, Felix; Kress, Julia A.; Edbauer, Dieter; Tüttelmann, Frank; Schindler, Christoph; Winter, Pia; Arzberger, Thomas; Müller, Ulrich; Danek, Adrian; Kretzschmar, Hans A.

doi:10.1007/s00702-015-1450-0

Cited by 9 publications

(3 citation statements)

References 12 publications

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“… 45–50 Yes Possibly damaging via in silico. [ 19 ] Roeber et al, 2015 W165C (G > C) Not available 37–47 Yes ↑Aβ42 and ↓Aβ40; elevated Aβ42/Aβ40 ratio [ 36 ] Campion et al, 1999 W165C (G > T) EOAD, a severe form of atrophies and rapid deterioration in cerebral and cerebellar 45 Yes ↓Aβ42 and ↓Aβ40; elevated Aβ42/Aβ40 ratio [ 37 ] Syama et al, 2018 W165G Not available 34–38 Yes Not available [ 39 ] Higuchi et al, 2000 L166H MRI: hippocampal atrophy and cortical atrophy. SPECT: bilateral hypometabolism in the parietal and frontal lobes.…”

Section: Discussionmentioning

confidence: 99%

A pathogenic PSEN1 Trp165Cys mutation associated with early-onset Alzheimer’s disease

et al. 2019

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Background: Presenilin-1 (PSEN1) is one of the causative genes for early onset Alzheimer's disease (EOAD). Recently, emerging studies reported several novel PSEN1 mutations among Asian. We describe a male with EOAD had a pathogenic PSEN1 mutation. Case presentation: A 53-year-old male presented with memory decline, followed by difficulty in finding ways. Patient had positive family history, since his mother and one of his brother was also affected with dementia. Brain magnetic resonance imaging (MRI) scan showed mild degree of atrophy of bilateral hippocampus and parietal lobe. 18 F-Florbetaben-PET (FBB-PET) revealed increased amyloid deposition in bilateral frontal, parietal, temporal lobe and precuneus. Whole exome analysis revealed a heterozygous, probably pathogenic PSEN1 (c.695G > T, p.W165C) mutation. Interestingly, Trp165Cys mutation is located in trans membrane (TM)-III region, which is conserved between PSEN1/PSEN2. In vitro studies revealed that PSEN1 Trp165Cys could result in disturbances in amyloid metabolism. This prediction was confirmed by structure predictions and previous in vitro studies that the p.Trp165Cys could result in decreased Aβ42/Aβ40 ratios. Conclusion: We report a case of EOAD having a pathogenic PSEN1 (Trp165Cys) confirmed with in silico and in vitro predictions.

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Section: Discussionmentioning

confidence: 99%

A pathogenic PSEN1 Trp165Cys mutation associated with early-onset Alzheimer’s disease

et al. 2019

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“…Presenilin proteins, PS1 and PS2, are constituents of the γ-secretase complex, which carry out amyloid precursor protein (APP) proteolytic processing [ 2 ]. Three new novel PS1 mutations have been uncovered in patients with a vast heterogeneity of clinical phenotypes [ 5 ]. Investigation of wild-type γ-secretase with six familial Alzheimer’s disease (FAD) mutants in PS1 and five FAD mutants in the Aβ peptide segment of the APP revealed that all mutations were associated with decreased γ-secretase activity and a reduced age of disease onset and death [ 6 ].…”

Section: γ-Secretase Activity Of Presenilinmentioning

confidence: 99%

Presenilins as Drug Targets for Alzheimer’s Disease—Recent Insights from Cell Biology and Electrophysiology as Novel Opportunities in Drug Development

Duncan

Song

Koulen

2018

IJMS

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A major cause underlying familial Alzheimer’s disease (AD) are mutations in presenilin proteins, presenilin 1 (PS1) and presenilin 2 (PS2). Presenilins are components of the γ-secretase complex which, when mutated, can affect amyloid precursor protein (APP) processing to toxic forms of amyloid beta (Aβ). Consequently, presenilins have been the target of numerous and varied research efforts to develop therapeutic strategies for AD. The presenilin 1 gene harbors the largest number of AD-causing mutations resulting in the late onset familial form of AD. As a result, the majority of efforts for drug development focused on PS1 and Aβ. Soon after the discovery of the major involvement of PS1 and PS2 in γ-secretase activity, it became clear that neuronal signaling, particularly calcium ion (Ca2+) signaling, is regulated by presenilins and impacted by mutations in presenilin genes. Intracellular Ca2+ signaling not only controls the activity of neurons, but also gene expression patterns, structural functionality of the cytoskeleton, synaptic connectivity and viability. Here, we will briefly review the role of presenilins in γ-secretase activity, then focus on the regulation of Ca2+ signaling, oxidative stress, and cellular viability by presenilins within the context of AD and discuss the relevance of presenilins in AD drug development efforts.

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“…The age of onset may be variable; several cases were related to a young disease onset (late twenties or early thirties), such as Leu85Pro [11], His163Pro [12] or Met233Val [13]. Meanwhile, other mutations, such as Met84Val [14] Ala164Val [15] or Phe175Ser [16], were associated with late disease onset (late sixties and seventies). In addition to the EOAD phenotypes, several different symptoms were related to PSEN1 mutations, including myoclonus, seizures, extrapyramidal symptoms, spastic paraparesis and behavioral and language dysfunctions [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Presenilin-1 (PSEN1) Mutations: Clinical Phenotypes beyond Alzheimer’s Disease

Yang

Bagyinszky

2023

IJMS

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Presenilin 1 (PSEN1) is a part of the gamma secretase complex with several interacting substrates, including amyloid precursor protein (APP), Notch, adhesion proteins and beta catenin. PSEN1 has been extensively studied in neurodegeneration, and more than 300 PSEN1 mutations have been discovered to date. In addition to the classical early onset Alzheimer’s disease (EOAD) phenotypes, PSEN1 mutations were discovered in several atypical AD or non-AD phenotypes, such as frontotemporal dementia (FTD), Parkinson’s disease (PD), dementia with Lewy bodies (DLB) or spastic paraparesis (SP). For example, Leu113Pro, Leu226Phe, Met233Leu and an Arg352 duplication were discovered in patients with FTD, while Pro436Gln, Arg278Gln and Pro284Leu mutations were also reported in patients with motor dysfunctions. Interestingly, PSEN1 mutations may also impact non-neurodegenerative phenotypes, including PSEN1 Pro242fs, which could cause acne inversa, while Asp333Gly was reported in a family with dilated cardiomyopathy. The phenotypic diversity suggests that PSEN1 may be responsible for atypical disease phenotypes or types of disease other than AD. Taken together, neurodegenerative diseases such as AD, PD, DLB and FTD may share several common hallmarks (cognitive and motor impairment, associated with abnormal protein aggregates). These findings suggested that PSEN1 may interact with risk modifiers, which may result in alternative disease phenotypes such as DLB or FTD phenotypes, or through less-dominant amyloid pathways. Next-generation sequencing and/or biomarker analysis may be essential in clearly differentiating the possible disease phenotypes and pathways associated with non-AD phenotypes.

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Three novel presenilin 1 mutations marking the wide spectrum of age at onset and clinical patterns in familial Alzheimer’s disease

Cited by 9 publications

References 12 publications

A pathogenic PSEN1 Trp165Cys mutation associated with early-onset Alzheimer’s disease

A pathogenic PSEN1 Trp165Cys mutation associated with early-onset Alzheimer’s disease

Presenilins as Drug Targets for Alzheimer’s Disease—Recent Insights from Cell Biology and Electrophysiology as Novel Opportunities in Drug Development

Presenilin-1 (PSEN1) Mutations: Clinical Phenotypes beyond Alzheimer’s Disease

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