Retrograde transport of γ‐secretase from endosomes to the trans‐Golgi network regulates Aβ42 production

Kanatsu, Kunihiko; Hori, Yukiko; Ebinuma, Ihori; Chiu, Yung Wen; Tomita, Taisuke

doi:10.1111/jnc.14477

Cited by 11 publications

(11 citation statements)

References 40 publications

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“…Alternatively, retrograde transport to the trans-Golgi network is also reported. This can be mediated through retromer as well as retromer-independent pathway that is affected by retro-2 [92]. As all these different transport routes can affect the Aβ levels and profiles, it is of the utmost importance to further systematically investigate these transport itineraries and identify those factors that can influence them.…”

Section: "Location Location Location"mentioning

confidence: 99%

Contribution of the Presenilins in the cell biology, structure and function of γ-secretase

Escamilla-Ayala

Wouters

Sannerud

et al. 2020

Seminars in Cell & Developmental Biology

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Secretase cleavage is essential for many biological processes and its dysregulation is linked to disease, including cancer and Alzheimer's disease. Therefore, understanding the regulation of its activity is of major importance to improve drug design and develop novel therapeutics. γ-Secretase belongs to the family of intramembrane cleaving proteases (i-CLiPs), which cleaves its substrates in a process termed regulated intramembrane proteolysis (RIP). During RIP, type-I transmembrane proteins are first cleaved within their ectodomain by a sheddase and then within their transmembrane domain by γ-secretase. γ-Secretase is composed of four integral membrane proteins that are all essential for its function: presenilin (PSEN), anterior pharynx defective 1 (APH1), nicastrin (NCT) and presenilin enhancer 2 (PEN-2). Given the presence of two PSEN homologues (PSEN1 & 2) and several APH1 isoforms, a heterogeneity exists in cellular γ-secretase complexes. It is becoming clear that each of these complexes has overlapping as well as distinct biological characteristics. This review summarizes our current knowledge on complex formation, trafficking, subcellular localization, interactors and the structure of γ-secretase, with a focus, when possible or known, on the contribution of PSEN1 and PSEN2 herein.

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Section: "Location Location Location"mentioning

confidence: 99%

Contribution of the Presenilins in the cell biology, structure and function of γ-secretase

Escamilla-Ayala

Wouters

Sannerud

et al. 2020

Seminars in Cell & Developmental Biology

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“…Consequently, there are distinct Aβ-peptides produced at the PM or in endosome/lysosomes ( Figure 1 B). Changes in γ-secretase transport with in particular its retrograde transport also have been shown to contribute to the generation of Aβ 42 [ 43 , 44 ]. Interestingly, overexpression of the retromer componnt Vps35 in an AD mouse-model completely rescued the phenotype (as it normalized the Aβ formation, synaptic and cognitive functions as well as neuro-inflammation) [ 45 ].…”

Section: From Early Endosome To Mvb: a Sorting Station For App Andmentioning

confidence: 99%

Transmissible Endosomal Intoxication: A Balance between Exosomes and Lysosomes at the Basis of Intercellular Amyloid Propagation

2020

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In Alzheimer′s disease (AD), endolysosomal dysfunctions are amongst the earliest cellular features to appear. Each organelle of the endolysosomal system, from the multivesicular body (MVB) to the lysosome, contributes to the homeostasis of amyloid precursor protein (APP) cleavage products including β-amyloid (Aβ) peptides. Hence, this review will attempt to disentangle how changes in the endolysosomal system cumulate to the generation of toxic amyloid species and hamper their degradation. We highlight that the formation of MVBs and the generation of amyloid species are closely linked and describe how the molecular machineries acting at MVBs determine the generation and sorting of APP cleavage products towards their degradation or release in association with exosomes. In particular, we will focus on AD-related distortions of the endolysomal system that divert it from its degradative function to favour the release of exosomes and associated amyloid species. We propose here that such an imbalance transposed at the brain scale poses a novel concept of transmissible endosomal intoxication (TEI). This TEI would initiate a self-perpetuating transmission of endosomal dysfunction between cells that would support the propagation of amyloid species in neurodegenerative diseases.

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“…The loss of CIB1 increases the internalization of γ-secretase as well as the Aβ production (Figure 7, right panel). Given that the previous studies demonstrated that the subcellular localization of γ-secretase could affect its activity within a cell, 15,39 CIB1 may be able to retain active γ-secretase at the plasma membrane or in early endosomes, where γ-secretase has low activity, leading to the suppression of Aβ production. On the contrary, under conditions of low CIB1 expression, γ-secretase may be internalized more to late endosomes and lysosomes, resulting in increased Aβ production.…”

Section: Discussionmentioning

confidence: 99%

Identification of calcium and integrin‐binding protein 1 as a novel regulator of production of amyloid β peptide using CRISPR/Cas9‐based screening system

et al. 2020

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The aberrant metabolism of amyloid β peptide (Aβ) has been implicated in the etiology of Alzheimer disease (AD). Aβ is produced via the sequential cleavage of amyloid precursor protein (APP) by β‐ and γ‐secretases. However, the precise regulatory mechanism of Aβ generation still remains unclear. To gain a better understanding of the molecular mechanism of Aβ production, we established a genetic screening method based on the CRISPR/Cas9 system to identify novel regulators of Aβ production. We successfully identified calcium and integrin‐binding protein 1 (CIB1) as a potential negative regulator of Aβ production. The disruption of Cib1 significantly upregulated Aβ levels. In addition, immunoprecipitation experiments demonstrated that CIB1 interacts with the γ‐secretase complex. Moreover, the disruption of Cib1 specifically reduced the cell‐surface localization of mature Nicastrin (Nct), which is a component of the γ‐secretase complex, without changing the intrinsic activity of γ‐secretase. Finally, we confirmed using the single‐cell RNA‐seq data in human that CIB1 mRNA level in neuron was decreased in the early stage of AD. Taken together, our results indicate that CIB1 regulates Aβ production via controlling the subcellular localization of γ‐secretase, suggesting CIB1 is involved in the development of AD.

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Retrograde transport of γ‐secretase from endosomes to the trans‐Golgi network regulates Aβ42 production

Abstract: Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/.

Cited by 11 publications

References 40 publications

Contribution of the Presenilins in the cell biology, structure and function of γ-secretase

Contribution of the Presenilins in the cell biology, structure and function of γ-secretase

Transmissible Endosomal Intoxication: A Balance between Exosomes and Lysosomes at the Basis of Intercellular Amyloid Propagation

Identification of calcium and integrin‐binding protein 1 as a novel regulator of production of amyloid β peptide using CRISPR/Cas9‐based screening system

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