γ-Secretase Associated with Lipid Rafts

Matsumura, Nobutaka; Takami, Mako; Okochi, Masayasu; Wada‐Kakuda, Satoko; Fujiwara, H.; Tagami, Shinji; Funamoto, Satoru; Ihara, Yasuo; Morishima-Kawashima, Maho

doi:10.1074/jbc.m113.510131

Cited by 100 publications

(101 citation statements)

References 36 publications

(93 reference statements)

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“…Thus, it is possible that C99 is delivered to ER via a similar mechanism, where it regulates the interaction between ER and mitochondria. Furthermore, the localization of C99 at MAM clarifies why C99, an ER‐localized protein (Matsumura et al , 2014), was also detected in mitochondria (Devi & Ohno, 2012). Similarly, since C99 processing occurs at MAM, this could explain why Aβ has been found to colocalize with mitochondria (Hansson Petersen et al , 2008; Xie et al , 2013).…”

Section: Discussionmentioning

confidence: 73%

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

et al. 2017

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In the amyloidogenic pathway associated with Alzheimer disease (AD), the amyloid precursor protein (APP) is cleaved by β‐secretase to generate a 99‐aa C‐terminal fragment (C99) that is then cleaved by γ‐secretase to generate the β‐amyloid (Aβ) found in senile plaques. In previous reports, we and others have shown that γ‐secretase activity is enriched in mitochondria‐associated endoplasmic reticulum (ER) membranes (MAM) and that ER–mitochondrial connectivity and MAM function are upregulated in AD. We now show that C99, in addition to its localization in endosomes, can also be found in MAM, where it is normally processed rapidly by γ‐secretase. In cell models of AD, however, the concentration of unprocessed C99 increases in MAM regions, resulting in elevated sphingolipid turnover and an altered lipid composition of both MAM and mitochondrial membranes. In turn, this change in mitochondrial membrane composition interferes with the proper assembly and activity of mitochondrial respiratory supercomplexes, thereby likely contributing to the bioenergetic defects characteristic of AD.

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Section: Discussionmentioning

confidence: 73%

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

et al. 2017

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“…The reason for this is unknown, although γ-secretase may be compensating for reduced cleavage through one of the two major pathways. Previous MS studies have demonstrated that the majority of Aβ47 is eventually processed to Aβ40, through an Aβ43 intermediate (Matsumura et al, 2014). …”

Section: Resultsmentioning

confidence: 99%

“…Mass spectrometry studies have identified a complex mixture of products generated from γ-secretase’s cleavage of the transmembrane domain of APP (Matsumura et al, 2014). Looking at the formation of these products over time, it is apparent that the TMD of APP is mostly processed via two major pathways.…”

Section: Introductionmentioning

confidence: 99%

“…The two major pathways are therefore Aβ49 → Aβ46 → Aβ43 → Aβ40 and Aβ48 → Aβ45 → Aβ42 (Figure 1A) (Fernandez et al, 2014; Takami et al, 2009). There are, however, other Aβ species generated by γ-secretase through usually minor and sometimes overlapping, alternative pathways (Matsumura et al, 2014; Olsson et al, 2014). Importantly a shorter peptide, Aβ38, can be formed from both major pathways, originating from Aβ42 or Aβ43 (Okochi et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…Importantly a shorter peptide, Aβ38, can be formed from both major pathways, originating from Aβ42 or Aβ43 (Okochi et al, 2013). Additionally, a third, sparingly used site of ε cleavage can lead to the production of Aβ47, which rather than being processed to Aβ44 is instead mostly cleaved to Aβ43, subsequently generating Aβ40 (Aβ47 → Aβ43 → Aβ40) (Matsumura et al, 2014).

10.7554/eLife.17578.003Figure 1.Tripeptide fragments of APP inhibit γ-secretase.( A ) Schematic diagram of the major sequential cleavage pathways of the transmembrane domain of APP (Aβ49 → Aβ46 → Aβ43 → Aβ40 in red and Aβ48 → Aβ45 → Aβ42 in blue).…”

Section: Introductionmentioning

confidence: 99%

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The amyloid-beta forming tripeptide cleavage mechanism of γ-secretase

Bolduc

Montagna

Seghers

et al. 2016

eLife

144

204

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γ-secretase is responsible for the proteolysis of amyloid precursor protein (APP) into short, aggregation-prone amyloid-beta (Aβ) peptides, which are centrally implicated in the pathogenesis of Alzheimer’s disease (AD). Despite considerable interest in developing γ-secretase targeting therapeutics for the treatment of AD, the precise mechanism by which γ-secretase produces Aβ has remained elusive. Herein, we demonstrate that γ-secretase catalysis is driven by the stabilization of an enzyme-substrate scission complex via three distinct amino-acid-binding pockets in the enzyme’s active site, providing the mechanism by which γ-secretase preferentially cleaves APP in three amino acid increments. Substrate occupancy of these three pockets occurs after initial substrate binding but precedes catalysis, suggesting a conformational change in substrate may be required for cleavage. We uncover and exploit substrate cleavage preferences dictated by these three pockets to investigate the mechanism by which familial Alzheimer’s disease mutations within APP increase the production of pathogenic Aβ species.DOI: http://dx.doi.org/10.7554/eLife.17578.001

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The presenilin 1 mutation P436S causes familial Alzheimer's disease with elevated Aβ43 and atypical clinical manifestations

Arber,

Belder,

Tomczuk

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONFamilial Alzheimer's disease (fAD) is heterogeneous in terms of age at onset and clinical presentation. A greater understanding of the pathogenicity of fAD variants and how these contribute to heterogeneity will enhance our understanding of the mechanisms of AD more widely.METHODSTo determine the pathogenicity of the unclassified PSEN1 P436S mutation, we studied an expanded kindred of eight affected individuals, with magnetic resonance imaging (MRI) (two individuals), patient‐derived induced pluripotent stem cell (iPSC) models (two donors), and post‐mortem histology (one donor).RESULTSAn autosomal dominant pattern of inheritance of fAD was seen, with an average age at symptom onset of 46 years and atypical features. iPSC models and post‐mortem tissue supported high production of amyloid beta 43 (Aβ43). PSEN1 peptide maturation was unimpaired.DISCUSSIONWe confirm that the P436S mutation in PSEN1 causes atypical fAD. The location of the mutation in the critical PSEN1 proline‐alanine‐leucine‐proline (PALP) motif may explain the early age at onset despite appropriate protein maturation.Highlights PSEN1 P436S mutations cause familial Alzheimer's disease. This mutation is associated with atypical clinical presentation. Induced pluripotent stem cells (iPSCs) and post‐mortem studies support increased amyloid beta (Aβ43) production. Early age at onset highlights the importance of the PALP motif in PSEN1 function.

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γ-Secretase Associated with Lipid Rafts

Cited by 100 publications

References 36 publications

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

The amyloid-beta forming tripeptide cleavage mechanism of γ-secretase

The presenilin 1 mutation P436S causes familial Alzheimer's disease with elevated Aβ43 and atypical clinical manifestations

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