Identification of New Presenilin Gene Mutations in Early-Onset Familial Alzheimer Disease

Tedde, Andrea; Nacmias, Benedetta; Ciantelli, Monica; Forleo, Paolo; Cellini, Elena; Bagnoli, Silvia; Piccini, Carolina; Caffarra, Paolo; Ghidoni, Enrico; Paganini, Marco; Bracco, Laura; Sorbi, Sandro

doi:10.1001/archneur.60.11.1541

Cited by 44 publications

(27 citation statements)

References 18 publications

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“…Importantly, all 3 transmembrane cysteines are well-conserved (Fig. 2B) and Cys92 and Cys410 are sites of FAD mutations (42,43). Only two of these native cysteines, Cys410 and Cys419, are in the PS1-CTF, and both are located in TMD8.…”

Section: Disulfide Oxidation Of C92s C410s and C419s Ps1 Mutantsmentioning

confidence: 98%

Deducing the Transmembrane Domain Organization of Presenilin-1 in γ-Secretase by Cysteine Disulfide Cross-Linking

et al. 2006

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Abstractγ-Secretase is a founding member of membrane-embedded aspartyl proteases that cleave substrates within transmembrane domains, and this enzyme is an important target for the development of therapeutics for Alzheimer's disease. The structure of γ-secretase and its precise catalytic mechanism still remain largely unknown. γ-Secretase is a complex of four integral membrane proteins, with presenilin (PS) as the catalytic component. To gain structural and functional information about the 9-transmembrane domain (TMD) presenilin, we employed a cysteine mutagenesis/disulfidecrosslinking approach. Here we report that native Cys92 is close to both Cys410 and Cys419, strongly implying that TMD1 and TMD8 are adjacent to each other. This structural arrangement also suggests that TMD8 is distorted from an ideal helix. Importantly, binding of an active-site directed inhibitor, but not a docking-site directed inhibitor, reduces the ability of the native cysteine pairs of PS1 to crosslink upon oxidation. These findings suggest that the conserved cysteines of TMD1 and TMD8 contribute to or allosterically interact with the active site of γ-secretase.Accumulation of the amyloid β-protein (Aβ) is one of the defining pathological features of Alzheimer's disease. Aβ is produced from the amyloid β-protein precursor (APP) as a result of sequential proteolytic cleavages first by β-secretase (1) and then by γ-secretase (2). γ-Secretase is an aspartyl transmembrane protease that cleaves a number of type I membrane protein substrates, including APP and Notch, in the middle of their transmembrane domains in a poorly understood process of hydrolysis within a hydrophobic environment (3). γ-Secretase is composed of four transmembrane proteins, Aph-1, Pen-2, Nicastrin (NCT) (4-10) and presenilin (PS), which is ostensibly the catalytic component of an unusual aspartyl protease (3,11,12). Despite substantial progress in establishing the full identity of γ-secretase (7-9,13, 14) and the step-wise assembly of the γ-secretase complex (7,15,16), the molecular structure of the protease complex or even any of its individual components remains unknown. PS, as the catalytic component, is of major interest, but only some indirect evidence about its structural arrangement has been reported to date. Indeed, it has only very recently been established that PS1 is a 9-TMD protein (17,18). PS is endoproteolytically processed into an N-terminal fragment (NTF) and C-terminal fragment (CTF) (19). These fragments are metabolically stable, remain associated, and their formation is tightly regulated (20). Also, it is widely † This work was supported by grants to M.S.W. from the National Institutes of Health (NS41355 and AG17574) and the Alzheimer's Association (IIRG-02-4047) and a fellowship to H. L. (Wenner-Gren Foundation in Sweden). An understanding of the mechanism of γ-secretase proteolysis requires a detailed description of the three-dimensional organization of its transmembrane domains. In light of inherent difficulties in obtaining a structure of γ-secr...

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Section: Disulfide Oxidation Of C92s C410s and C419s Ps1 Mutantsmentioning

confidence: 98%

Deducing the Transmembrane Domain Organization of Presenilin-1 in γ-Secretase by Cysteine Disulfide Cross-Linking

et al. 2006

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“…We examined whether the null mutations sel-12(ty11) and sel-12(ok2078) or the missense mutation sel-12(ar131), which is a conserved change identified in FAD patients (Tedde et al 2003), causes a different behavioral response to levamisole compared to wild-type animals. Upon exposure to levamisole for 70 min, only 24.4% of sel-12(ar131), 16.3% of sel-12(ty11), and 14.8% of sel-12(ok2078) animals were moving compared to 58.5% of wild-type animals ( Figure 1A).…”

Section: Sel-12 Mutants Are Hypersensitive To Levamisolementioning

confidence: 99%

A γ-Secretase Independent Role for Presenilin in Calcium Homeostasis Impacts Mitochondrial Function and Morphology in Caenorhabditis elegans

Sarasija¹,

Norman

2015

Genetics

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Mutations in the presenilin (PSEN) encoding genes (PSEN1 and PSEN2) occur in most early onset familial Alzheimer's Disease. Despite the identification of the involvement of PSEN in Alzheimer's Disease (AD) 20 years ago, the underlying role of PSEN in AD is not fully understood. To gain insight into the biological function of PSEN, we investigated the role of the PSEN homolog SEL-12 in Caenorhabditis elegans. Using genetic, cell biological, and pharmacological approaches, we demonstrate that mutations in sel-12 result in defects in calcium homeostasis, leading to mitochondrial dysfunction. Moreover, consistent with mammalian PSEN, we provide evidence that SEL-12 has a critical role in mediating endoplasmic reticulum (ER) calcium release. Furthermore, we found that in SEL-12-deficient animals, calcium transfer from the ER to the mitochondria leads to fragmentation of the mitochondria and mitochondrial dysfunction. Additionally, we show that the impact that SEL-12 has on mitochondrial function is independent of its role in Notch signaling, g-secretase proteolytic activity, and amyloid plaques. Our results reveal a critical role for PSEN in mediating mitochondrial function by regulating calcium transfer from the ER to the mitochondria.KEYWORDS Caenorhabditis elegans; calcium; endoplasmic reticulum; mitochondria; presenilin M ITOCHONDRIA are highly dynamic organelles that are responsible for a myriad of functions including ATP production, generation and metabolism of reactive oxygen species (ROS), and apoptosis (Detmer and Chan 2007). Thus cells, in particular muscle cells and neurons due to their highenergy demands, are extremely reliant on mitochondrial function. Mitochondria also play a critical role in calcium homeostasis by acting as a calcium buffer. Calcium, in turn, regulates mitochondrial morphology, activity, and movement. The relevance of mitochondria is highlighted by the fact that many neurodegenerative diseases, such as Parkinson's and Alzheimer's Disease (AD) are characterized by abnormal mitochondrial activity and morphology (Cali et al. 2012).Mutations in the genes encoding presenilins (PSENs), PSEN1 and PSEN2, are the most common cause of early onset familial Alzheimer's Disease (FAD). PSENs are 50-kDa multipass transmembrane proteins that reside predominantly on the endoplasmic reticulum (ER) (Bezprozvanny and Mattson 2008) and have been shown to be enriched in an ER subcompartment that is in contact with mitochondria (Area-Gomez et al. 2009). Although altered PSEN function has been known to have a role in AD for 20 years (Sherrington et al. 1995), the functional consequences of mutations in PSENs are controversial and not understood. The prevailing model for the pathogenesis of AD is the "amyloid hypothesis," which states that an increase in b amyloid (Ab) 42 peptide is the major cause of neuronal degradation in AD (Hardy and Selkoe 2002); support for this hypothesis stems from the accumulation of amyloid plaques in the brains of AD patients (Hardy 2006). In addition to the "amyloid hypot...

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“…Subjects 1 and 2 belonged to a family with Cys92Ser mutation whose proband was referred to medical attention at 49 years of age for ''depression'' [17]. Subjects 3, 4 and 5 are members (one brother and one sister and nephew of a grandmother's uncle) of a large family with PS1 Leu392Val missense mutation [18].…”

Section: Subjectsmentioning

confidence: 99%

Early structural changes in individuals at risk of familial Alzheimer’s disease: a volumetry and magnetization transfer MR imaging study

et al. 2009

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Presenilin 1 (PS1) mutation carriers provide the opportunity to asses early features of neurodegeneration in familial Alzheimer's disease (AD). Gray matter (GM) regional volume loss and decrease of magnetization transfer ratio (MTR) consistent with microstructural changes have been reported in sporadic AD. We performed a regional volumetric and MTR analysis in carriers of PS1 mutations. Six non-demented mutated PS1 carriers (5 with memory deficits) and 14 healthy subjects were examined with high resolution T1-weighted images for volumetry and with T2* weighted images for MTR. Cortical GM volume and MTR values were derived. Compared to healthy controls, the GM volume of the left temporal and inferior parietal cortex and the MTR of the temporal cortex bilaterally were significantly decreased in PS1 gene carriers. In the latter, the temporal lobe MTR showed a trend for correlation with memory and executive function scores. Early neurodegeneration in non-demented subjects at risk for familial AD may be associated with atrophy and decreased MTR in the temporal cortex.

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Identification of New Presenilin Gene Mutations in Early-Onset Familial Alzheimer Disease

Cited by 44 publications

References 18 publications

Deducing the Transmembrane Domain Organization of Presenilin-1 in γ-Secretase by Cysteine Disulfide Cross-Linking

Deducing the Transmembrane Domain Organization of Presenilin-1 in γ-Secretase by Cysteine Disulfide Cross-Linking

A γ-Secretase Independent Role for Presenilin in Calcium Homeostasis Impacts Mitochondrial Function and Morphology in Caenorhabditis elegans

Early structural changes in individuals at risk of familial Alzheimer’s disease: a volumetry and magnetization transfer MR imaging study

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