GSAP modulates <i>γ</i>-secretase specificity by inducing conformational change in PS1

Wong, Eitan; Liao, George P.; Chang, Jerry C.; Xu, Peng; Li, Yueming; Greengard, Paul

doi:10.1101/461061

Cited by 4 publications

(6 citation statements)

References 21 publications

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“…11 γ-Secretase is able to cleave the APP C-99 transmembrane domain in the presence of an important protein known as γ-secretase activating protein or GSAP. 12,13 As reported in the literature, the presence of GSAP is one of the major determining conditions for the formation of Aβ plaques that leads to Alzheimer's disease. Thus, BACE-I, γ-secretase, and GSAP are three important protein targets which if inhibited can target AD.…”

Section: ■ Introductionmentioning

confidence: 93%

“…Whereas in the absence or knockout of GSAP, the presenilin-I adopts a different conformation that leads to reduced γ-secretase activity. 13 These works on GSAP highlight its importance as a promising target in Alzheimer's disease. In particular, the observation that inhibition of GSAP reduces the deposition of Aβ plaques in brain tissue points to its potential as a focus for therapeutic intervention.…”

Section: ■ Introductionmentioning

confidence: 99%

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Tracing the GSAP–APP C-99 Interaction Site in the β-Amyloid Pathway Leading to Alzheimer’s Disease

Angira

Chikhale

Mehta

et al. 2019

ACS Chem. Neurosci.

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Gamma secretase activating protein (GSAP) present in β-amyloid pathway orchestrates the formation of β-amyloid plaques by γ-secretase activation and is an emerging therapeutic target for the treatment of Alzheimer’s disease. It forms a ternary complex with γ-secretase and APP C-99. However, there are limited reports for the interaction of APP C-99 with GSAP. Here, we report the characterization of purified maltose binding protein (MBP) tagged human GSAP and its interaction with synthetic APP C-99 peptide fragments (712IATVIVITLVMLKKQ727 (712IQ727), 719TLVMLKKKQYTSIHHGVVEVDAAVT743 (719TT743) 734GVVEVDAAVTPEERHLSKMQQNGY757 (734GY757), and 746ERHLSKMQQNGYENPTYKFFEQMQN770 (746EN770)). The results emphasize the selective interaction of peptide (719TT743) with MBP-GSAP with a dissociation constant of 0.136 μM. Further, computational modeling of the GSAP–719TT743 complex finds an optimal bound pose of 719TT743 within an extended groove on the surface of GSAP. The preliminary results highlight the interaction between the two major proteins in the plausible ternary complex: APP C-99–GSAP−γ-secretase. It paves a futuristic path to investigate the GSAP–APP C-99 binding in detail and accentuates the role of GSAP in the β-amyloid pathway.

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Section: ■ Introductionmentioning

confidence: 93%

Section: ■ Introductionmentioning

confidence: 99%

Tracing the GSAP–APP C-99 Interaction Site in the β-Amyloid Pathway Leading to Alzheimer’s Disease

Angira

Chikhale

Mehta

et al. 2019

ACS Chem. Neurosci.

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“…We previously discovered a novel γ-secretase activating protein (GSAP) that participates in amyloidogenic processing without affecting Notch cleavage 30,31 . GSAP specifically regulates the γ-cleavage of APP through its interaction with the APP-CTF and presenilin 1 (PS1), the catalytic component of the γ-secretase complex 30 .…”

Section: Introductionmentioning

confidence: 99%

“…GSAP specifically regulates the γ-cleavage of APP through its interaction with the APP-CTF and presenilin 1 (PS1), the catalytic component of the γ-secretase complex 30 . Using an active-site-directed photoprobe, we demonstrated that the interaction between GSAP and PS1 favors γ-secretase to stay in its active conformation, which specifically increases the efficiency for γ-cleavage of APP without affecting Notch processing 31 . Mounting evidence suggests that PS1 also modulates Aβ production via regulating the sorting and trafficking of APP, and vice versa 5 .…”

Section: Introductionmentioning

confidence: 99%

GSAP Regulates Amyloid Beta Production through Modulation of Amyloid Precursor Protein Trafficking

Wong

et al. 2020

Preprint

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In addition to participating in γ-secretase activity, presenilin 1 (PS1) regulates trafficking and subcellular localization of β-amyloid precursor protein (APP). We previously showed that gamma-secretase activating protein (GSAP) selectively modulates γ-secretase activity by inducing conformational change in PS1. However, little is known whether and how GSAP might influence APP trafficking and consequent generation of β-amyloid (Aβ) peptides. Here, to explore whether GSAP has any role in regulating APP trafficking, and to systematically investigate the intracellular trafficking routes of APP, we paired total internal reflection fluorescence microscopy, high-speed line scanning microscopy, and 4D microscopy with comprehensive imaging analysis methodologies to depict the elusive modes of APP trafficking at a single-vesicle level. Mobility and diffusivity changes reveal the existence of two kinetically distinct pathways, classified into mobile and immobile pools, for vesicular APP trafficking, suggesting high association between immobile vesicle pool and amyloidogenic processing. GSAP knockdown significantly lowers immobile pool without overturning APP vesicle diffusivity, suggesting that GSAP affects vesicular APP trafficking by retaining APP in membrane microdomains known to favor amyloidogenic processing. Our study reveals a novel role of GSAP in the regulation of Aβ-peptide formation that modulates switching of APP vesicles between immobile and mobile pools, which may help identifying new therapeutic strategies to treat Alzheimer’s disease.

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“…Wong. E. et al worked on GSAP gene knockout in HEK293 cell lines and found that this had direct association with γ-secretase activity decrease which in turn caused reduction in Aβ generation [374,376,377]. Another study consisting of in vivo as well as ex vivo by György et al, on the mutation of APPswe by the application of CRISPR/ Cas9 using Streptococcus pyogenes revealed that disruption in APPswe lead to fall in Aβ level [374,378].…”

Section: Crispr-cas Systemmentioning

confidence: 99%

Gene Therapy Approach with an Emphasis on Growth Factors: Theoretical and Clinical Outcomes in Neurodegenerative Diseases

et al. 2021

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The etiology of many neurological diseases affecting the central nervous system (CNS) is unknown and still needs more effective and specific therapeutic approaches. Gene therapy has a promising future in treating neurodegenerative disorders by correcting the genetic defects or by therapeutic protein delivery and is now an attraction for neurologists to treat brain disorders, like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, spinocerebellar ataxia, epilepsy, Huntington's disease, stroke, and spinal cord injury. Gene therapy allows the transgene induction, with a unique expression in cells' substrate. This article mainly focuses on the delivering modes of genetic materials in the CNS, which includes viral and non-viral vectors and their application in gene therapy. Despite the many clinical trials conducted so far, data have shown disappointing outcomes. The efforts done to improve outcomes, efficacy, and safety in the identification of targets in various neurological disorders are also discussed here. Adapting gene therapy as a new therapeutic approach for treating neurological disorders seems to be promising, with early detection and delivery of therapy before the neuron is lost, helping a lot the development of new therapeutic options to translate to the clinic.

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GSAP modulates γ-secretase specificity by inducing conformational change in PS1

Cited by 4 publications

References 21 publications

Tracing the GSAP–APP C-99 Interaction Site in the β-Amyloid Pathway Leading to Alzheimer’s Disease

Tracing the GSAP–APP C-99 Interaction Site in the β-Amyloid Pathway Leading to Alzheimer’s Disease

GSAP Regulates Amyloid Beta Production through Modulation of Amyloid Precursor Protein Trafficking

Gene Therapy Approach with an Emphasis on Growth Factors: Theoretical and Clinical Outcomes in Neurodegenerative Diseases

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