Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Aβ 42/40 ratios

Walker, Emily; Martínez, Maribel; Brunkan, Anne L.; Goate, Alison M.

doi:10.1111/j.1471-4159.2004.02858.x

Cited by 161 publications

(146 citation statements)

References 38 publications

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“…Although already found in patients with LOAD, they were also identified in control databases European American EVS and European 1000 Genomes with a MAF of 0.1 and 0.26%, respectively, (c.389C4T) and of 0.37 and 0.01% (c.211C4T), respectively. Moreover, functional assays 14 and segregation analyses 15 were not in favor of a causative role in a Mendelian context.…”

Section: Psen1 and Psen2 Variantsmentioning

confidence: 93%

Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons

Nicolas¹,

Wallon²,

Charbonnier³

et al. 2015

Eur J Hum Genet

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Causative variants in APP, PSEN1 or PSEN2 account for a majority of cases of autosomal dominant early-onset Alzheimer disease (ADEOAD, onset before 65 years). Variant detection rates in other EOAD patients, that is, with family history of lateonset AD (LOAD) (and no incidence of EOAD) and sporadic cases might be much lower. We analyzed the genomes from 264 patients using whole-exome sequencing (WES) with high depth of coverage: 90 EOAD patients with family history of LOAD and no incidence of EOAD in the family and 174 patients with sporadic AD starting between 51 and 65 years. We found three PSEN1 and one PSEN2 causative, probably or possibly causative variants in four patients (1.5%). Given the absence of PSEN1, PSEN2 and APP causative variants, we investigated whether these 260 patients might be burdened with protein-modifying variants in 20 genes that were previously shown to cause other types of dementia when mutated. For this analysis, we included an additional set of 160 patients who were previously shown to be free of causative variants in PSEN1, PSEN2 and APP: 107 ADEOAD patients and 53 sporadic EOAD patients with an age of onset before 51 years. In these 420 patients, we detected no variant that might modify the function of the 20 dementia-causing genes. We conclude that EOAD patients with family history of LOAD and no incidence of EOAD in the family or patients with sporadic AD starting between 51 and 65 years have a low variant-detection rate in AD genes.

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Section: Psen1 and Psen2 Variantsmentioning

confidence: 93%

Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons

Nicolas¹,

Wallon²,

Charbonnier³

et al. 2015

Eur J Hum Genet

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“…We can conclude that the modulation of the ER-mitochondria interaction (i) does not require the enzymatic activity of PS2, (ii) does not require the presenilin endoproteolytic cut [because the equally effective PS2-D366A mutant also is devoid of this activity (28)], (iii) is not caused by ER Ca 2+ overload or depletion, (iv) does not result from an increase of the intrinsic Ca 2+ uptake capacity of mitochondria, and (v) does not correlate with modifications of Mfn2 levels.…”

Section: Discussionmentioning

confidence: 99%

Presenilin 2 modulates endoplasmic reticulum (ER)–mitochondria interactions and Ca ²⁺ cross-talk

Zampese¹,

Fasolato²,

Kipanyula³

et al. 2011

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

257

282

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Presenilin mutations are the main cause of familial Alzheimer's disease (FAD). Presenilins also play a key role in Ca 2+ homeostasis, and their FAD-linked mutants affect cellular Ca 2+ handling in several ways. We previously have demonstrated that FAD-linked presenilin 2 (PS2) mutants decrease the Ca 2+ content of the endoplasmic reticulum (ER) by inhibiting sarcoendoplasmic reticulum Ca 2+ -ATPase (SERCA) activity and increasing ER Ca 2+ leak. Here we focus on the effect of presenilins on mitochondrial Ca 2+ dynamics. By using genetically encoded Ca 2+ indicators specifically targeted to mitochondria (aequorin-and GFP-based probes) in SH-SY5Y cells and primary neuronal cultures, we show that overexpression or down-regulation of PS2, but not of presenilin 1 (PS1), modulates the Ca 2+ shuttling between ER and mitochondria, with its FAD mutants strongly favoring Ca 2+ transfer between the two organelles. This effect is not caused by a direct PS2 action on mitochondrial Ca 2+ -uptake machinery but rather by an increased physical interaction between ER and mitochondria that augments the frequency of Ca 2+ hot spots generated at the cytoplasmic surface of the outer mitochondrial membrane upon stimulation. This PS2 function adds further complexity to the multifaceted nature of presenilins and to their physiological role within the cell. We also discuss the importance of this additional effect of FAD-linked PS2 mutants for the understanding of FAD pathogenesis.fluorescent Ca 2+ probe | intracellular organelle tethering | fluorescence resonance energy transfer A lzheimer's disease (AD) is the most common form of dementia in developed countries. The pathogenesis of AD is still largely mysterious, and most basic research in the field is concentrated on rare genetic forms of familial AD (FAD). The majority of FAD cases are caused by point mutations in genes for two homologous proteins, presenilin 1 (PS1) and presenilin 2 (PS2), that are essential components of the γ-secretase complex responsible for the production of the amyloid β peptides (Aβ) (1).Evidence has accumulated suggesting that FAD is linked to an imbalance of cellular Ca 2+ homeostasis (see refs. 2 and 3 for recent reviews). In particular, presenilins appear to play a key role in the control of Ca 2+ concentration within the endoplasmic reticulum (ER), [Ca 2+ ] ER : (i) Several FAD-linked presenilin mutants altered the expression or sensitivity of ER Ca 2+ release channels [ryanodine receptor (RyR) and inositol 1,4,5-trisphosphate receptor (IP 3 R)] in cell lines, neurons, and brain microsomes (see ref. 4 for a recent review); (ii) the sarcoendoplasmic reticulum Ca 2+ ATPase (SERCA) has been proposed as a target of presenilins, although opposite regulatory effects have been reported (5, 6); and (iii) it has been suggested that WT presenilins, but not FAD-linked presenilin mutants, form low-conductance Ca 2+ leak channels in the ER membrane (7,8). This last finding supports the "Ca 2+ overload" hypothesis for FAD, which proposes that the reduced ER Ca 2+ leak c...

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“…Interestingly, the vast majority of PS mutations that impair NICD production also impair AICD production, indicating a general impairment of ␥-secretasedependent function that is not limited to a single substrate (Table 1) (11)(12)(13)(14)(15). This correspondence of the effects of mutations on liberation of NICD and AICD may reflect mechanistic similarities between the S3 and cleavages of Notch and APP, respectively, which occur at similar intramembranous positions near the cytoplasmic face of the plasma membrane.…”

Section: Fad-linked Ps Mutations Impairmentioning

confidence: 99%

“…Perhaps more surprisingly, numerous mutations in PS1 (e.g., N135D, L166P, M233T, P264L, G384A, and C410Y) and PS2 (e.g., T122P, N141I, M239V, and M239I) can cause significant reductions in the production of A␤40, often despite a concomitant increase in the production of A␤42 (12)(13)(14)(16)(17)(18)(19). The differential effect of PS mutations on alternative cleavage positions in the APP transmembrane domain seems not to represent a simple shift in substrate preference or specificity, because the degree of elevation in A␤42 levels with individual mutations does not correlate with the degree of depression in A␤40 or AICD levels (e.g., ref.…”

Section: Fad-linked Ps Mutations Impairmentioning

confidence: 99%

The presenilin hypothesis of Alzheimer's disease: Evidence for a loss-of-function pathogenic mechanism

Shen

Kelleher

2007

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

431

358

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Dominantly inherited mutations in the genes encoding presenilins (PS) and the amyloid precursor protein (APP) are the major causes of familial Alzheimer's disease (AD). The prevailing view of AD pathogenesis posits that accumulation of ␤-amyloid (A␤) peptides, particularly A␤42, is the central event triggering neurodegeneration. Emerging evidence, however, suggests that loss of essential functions of PS could better explain dementia and neurodegeneration in AD. First, conditional inactivation of PS in the adult mouse brain causes progressive memory loss and neurodegeneration resembling AD, whereas mouse models based on overproduction of A␤ have failed to produce neurodegeneration. Second, whereas pathogenic PS mutations enhance A␤42 production, they typically reduce A␤40 generation and impair other PS-dependent activities. Third, ␥-secretase inhibitors can enhance the production of A␤42 while blocking other ␥-secretase activities, thus mimicking the effects of PS mutations. Finally, PS mutations have been identified in frontotemporal dementia, which lacks amyloid pathology. Based on these and other observations, we propose that partial loss of PS function may underlie memory impairment and neurodegeneration in the pathogenesis of AD. We also speculate that A␤42 may act primarily to antagonize PS-dependent functions, possibly by operating as an active site-directed inhibitor of ␥-secretase.A lzheimer's disease (AD) is an age-related neurodegenerative dementia and is the most common cause of both neurodegeneration and dementia. Neurodegenerative dementias are characterized clinically by progressive impairment of cognitive abilities, which most prominently affects memory in AD. Neuronal and synaptic loss is the essential neuropathological feature common to different forms of neurodegenerative dementias, including AD, frontotemporal dementia (FTD) and Lewy body dementia (LBD). These diseases are distinguished neuropathologically by characteristic patterns of abnormal protein aggregation, such as the presence in the AD brain of cerebral cortical amyloid plaques and neurofibrillary tangles (NFTs). Extracellular amyloid plaques consist primarily of 40-to 42-residue ␤-amyloid (A␤) peptides (A␤40 and A␤42) derived from proteolytic processing of the amyloid precursor protein (APP). NFTs are intraneuronal inclusions composed of hyperphosphorylated forms of the microtubule-associated protein tau.Research on AD has been greatly stimulated by the identification of causative mutations in the genes encoding APP and presenilins (PS1 and PS2). Dominantly inherited missense mutations in APP increase the production of A␤ peptides and account for Ϸ10% of mutations identified in familial AD (FAD). PSs harbor Ϸ90% of identified FAD mutations, and many of these mutations increase the relative production of A␤42 peptides. The prevailing amyloid hypothesis posits that accumulation of A␤ peptides, particularly the more hydrophobic and aggregation-prone A␤42, triggers a pathogenic cascade, leading to neurodegeneration in AD (1). However, a...

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Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Aβ 42/40 ratios

Cited by 161 publications

References 38 publications

Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons

Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons

Presenilin 2 modulates endoplasmic reticulum (ER)–mitochondria interactions and Ca ²⁺ cross-talk

The presenilin hypothesis of Alzheimer's disease: Evidence for a loss-of-function pathogenic mechanism

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Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Aβ 42/40 ratios

Cited by 161 publications

References 38 publications

Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons

Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons

Presenilin 2 modulates endoplasmic reticulum (ER)–mitochondria interactions and Ca 2+ cross-talk

The presenilin hypothesis of Alzheimer's disease: Evidence for a loss-of-function pathogenic mechanism

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Presenilin 2 modulates endoplasmic reticulum (ER)–mitochondria interactions and Ca ²⁺ cross-talk