Retention in Endoplasmic Reticulum 1 (RER1) Modulates Amyloid-β (Aβ) Production by Altering Trafficking of γ-Secretase and Amyloid Precursor Protein (APP)

Park, Hyo-Jin; Shabashvili, Daniil E.; Nekorchuk, Michael; Shyqyriu, Eva; Jung, June‐Ho; Ladd, Thomas B.; Moore, Brenda D.; Felsenstein, Kevin M.; Golde, Todd E.; Kim, Seong Hun

doi:10.1074/jbc.m112.418442

Cited by 32 publications

(39 citation statements)

References 68 publications

(68 reference statements)

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“…Six out of these 13 mutants had functions related to ER and glycosylphosphatidylinositol (GPI) biosynthesis (FMN1, YIP1, CNE1, ERG27, GPI13, and GPI1), four were related to glycosylation and translocation (WBP1, OST1, OST3, SEC63), and three were functionally associated with COPI transport (SEC21, ERD2, RER1). Interestingly, of these human orthologs, four (SEC63 31 , KDELR1 32 , RER1 33 , and RPN1 34 ), which are the orthologs of yeast SEC63, ERD2, RER1, and OST1, respectively, have already been identified in previous studies for association with AD [31][32][33][34] .…”

Section: Resultsmentioning

confidence: 95%

FMN reduces Amyloid-β toxicity in yeast by regulating redox status and cellular metabolism

Chen

Hao

et al. 2020

Nat Commun

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Alzheimer's disease (AD) is defined by progressive neurodegeneration, with oligomerization and aggregation of amyloid-β peptides (Aβ) playing a pivotal role in its pathogenesis. In recent years, the yeast Saccharomyces cerevisiae has been successfully used to clarify the roles of different human proteins involved in neurodegeneration. Here, we report a genome-wide synthetic genetic interaction array to identify toxicity modifiers of Aβ42, using yeast as the model organism. We find that FMN1, the gene encoding riboflavin kinase, and its metabolic product flavin mononucleotide (FMN) reduce Aβ42 toxicity. Classic experimental analyses combined with RNAseq show the effects of FMN supplementation to include reducing misfolded protein load, altering cellular metabolism, increasing NADH/(NADH + NAD +) and NADPH/(NADPH + NADP +) ratios and increasing resistance to oxidative stress. Additionally, FMN supplementation modifies Htt103QP toxicity and α-synuclein toxicity in the humanized yeast. Our findings offer insights for reducing cytotoxicity of Aβ42, and potentially other misfolded proteins, via FMN-dependent cellular pathways.

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Section: Resultsmentioning

confidence: 95%

FMN reduces Amyloid-β toxicity in yeast by regulating redox status and cellular metabolism

Chen

Hao

et al. 2020

Nat Commun

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“…SH‐SY5Y (American Type Culture Collection, ATCC) and HEK293 cells (Park et al , ), and mouse embryonic fibroblast (MEF) cells were cultured as recommended by ATCC. N2a‐ANPP cells (Kim et al , ) were maintained in 200 μg/ml hygromycin B (Life Technologies) and 200 μg/ml G418 (Life Technologies).…”

Section: Methodsmentioning

confidence: 99%

“…Human Aβ ELISA using conditioned cell culture medium and rodent Aβ ELISA using mouse forebrain homogenates were performed as described previously (Lanz & Schachter, , ; Levites et al , ; Yohrling et al , ; Park et al , ). Immulon 4HBX flat bottom 96‐well plates (Thermo Scientific) were coated with either monoclonal antibodies specific to Aβ40 (13.1.1, human Aβ35–40 specific), Aβ42 (2.1.3, human Aβ35–42 specific), or total Aβ (AB5, human Aβ1–16 specific), and blocked with 1% BSA.…”

Section: Methodsmentioning

confidence: 99%

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The stress response neuropeptide CRF increases amyloid‐β production by regulating γ‐secretase activity

et al. 2015

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The biological underpinnings linking stress to Alzheimer's disease (AD) risk are poorly understood. We investigated how corticotrophin releasing factor (CRF), a critical stress response mediator, influences amyloid-b (Ab) production. In cells, CRF treatment increases Ab production and triggers CRF receptor 1 (CRFR1) and c-secretase internalization. Co-immunoprecipitation studies establish that c-secretase associates with CRFR1; this is mediated by b-arrestin binding motifs. Additionally, CRFR1 and c-secretase co-localize in lipid raft fractions, with increased c-secretase accumulation upon CRF treatment. CRF treatment also increases c-secretase activity in vitro, revealing a second, receptorindependent mechanism of action. CRF is the first endogenous neuropeptide that can be shown to directly modulate c-secretase activity. Unexpectedly, CRFR1 antagonists also increased Ab. These data collectively link CRF to increased Ab through c-secretase and provide mechanistic insight into how stress may increase AD risk. They also suggest that direct targeting of CRF might be necessary to effectively modulate this pathway for therapeutic benefit in AD, as CRFR1 antagonists increase Ab and in some cases preferentially increase Ab42 via complex effects on c-secretase.

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“…Furthermore, we find that retention in endoplasmic reticulum 1 (Rer1) is the direct target of Ttyh1 action, providing a potential mechanism by which Ttyh1 influences the Notch signaling pathway and thereby brain development. Rer1 has been known to exist in the ER and cis-Golgi and have roles in the regulation of c-secretase activity [17][18][19], intracellular rhodopsin trafficking [20], alpha-synuclein degradation [21], ER retention of peripheral myelin protein 22 (PMP22) [22], and the quality control of some voltage-gated sodium channels [23]. Since Notch has been known to be implicated in tumor progression in the adult, our study should also help better understanding of the molecular basis involved in Ttyh1-implicated phenotypic outcomes in other cellular events such as oncogenesis.…”

Section: Introductionmentioning

confidence: 99%

Ttyh1 regulates embryonic neural stem cell properties by enhancing the Notch signaling pathway

et al. 2018

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Despite growing evidence linking tweety-homologue 1 (Ttyh1) to normal mammalian brain development and cell proliferation, its exact role has not yet been determined. Here, we show that Ttyh1 is required for the maintenance of neural stem cell (NSC) properties as assessed by neurosphere formation and analyses of cell localization after electroporation. We find that enhanced Ttyh1-dependent stemness of NSCs is caused by enhanced γ-secretase activity resulting in increased levels of Notch intracellular domain (NICD) production and activation of Notch targets. This is a unique function of Ttyh1 among all other Ttyh family members. Molecular analyses revealed that Ttyh1 binds to the regulator of γ-secretase activity Rer1 in the endoplasmic reticulum and thereby destabilizes Rer1 protein levels. This is the key step for Ttyh1-dependent enhancement of γ-secretase activity, as Rer1 overexpression completely abolishes the effects of Ttyh1 on NSC maintenance. Taken together, these findings indicate that Ttyh1 plays an important role during mammalian brain development by positively regulating the Notch signaling pathway through the downregulation of Rer1.

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Retention in Endoplasmic Reticulum 1 (RER1) Modulates Amyloid-β (Aβ) Production by Altering Trafficking of γ-Secretase and Amyloid Precursor Protein (APP)

Cited by 32 publications

References 68 publications

FMN reduces Amyloid-β toxicity in yeast by regulating redox status and cellular metabolism

FMN reduces Amyloid-β toxicity in yeast by regulating redox status and cellular metabolism

The stress response neuropeptide CRF increases amyloid‐β production by regulating γ‐secretase activity

Ttyh1 regulates embryonic neural stem cell properties by enhancing the Notch signaling pathway

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