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

Angira, Deekshi; Chikhale, Rupesh; Mehta, Kapilkumar; Bryce, Richard A.; Thiruvenkatam, Vijay

doi:10.1021/acschemneuro.9b00332

Cited by 10 publications

(17 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Immunoblot analysis confirmed that GSAP co-precipitated with full-length APP and APP-CTF in HEK293T cells (Fig. 8a, top rows), demonstrating that APP C-terminus is essential for its interaction with GSAP 54 . Given our previous findings that GSAP is processed to release a C-terminal 16 kDa active form (GSAP-16K) 30 , we asked if GSAP interacts with APP through the GSAP-16K domain.…”

Section: Resultsmentioning

confidence: 68%

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

Wong

et al. 2020

Preprint

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 68%

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

Wong

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Recently, we observed that APP trafficking and partitioning in neuronal cells is regulated by GSAP (Chang et al, 2020), which may occur through the novel GSAP/Fe65/APP/PP1 protein complex described here. Since conflicting results have been reported with respect to the direct interaction of GSAP and APP, our current data favor a molecular model where Fe65 recruits GSAP:PP1 to dephosphorylate APP and regulate its trafficking and partitioning to lipid rafts (Angira et al, 2019; Deatherage et al, 2012; Savolainen et al, 2015). It would be interesting to further explore intermolecular interactions within the GSAP:Fe65:APP:PP1 protein complex and investigate how this complex regulates APP trafficking and partitioning.…”

Section: Resultsmentioning

confidence: 55%

“…Furthermore, genetic knockdown or pharmacological inhibition of GSAP lowers amyloid plaque deposition and tau phosphorylation in AD mouse models (Chu et al, 2014; Chu et al, 2015; He et al, 2010). Recently, it has been reported that GSAP physically interacts with amyloid precursor protein (APP) to regulate amyloid-β generation (Angira et al, 2019). In addition to increased GSAP levels observed in AD mouse models (Chu et al, 2015), GSAP up-regulation has also been reported in neurodegenerative contexts such as Down Syndrome (Chu et al, 2016), which is obligately associated with Aβ plaque pathology due to triplication of human Chromosome 21 harboring APP (Wiseman et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

GSAP regulates mitochondrial function through the Mitochondria-associated ER membrane in the pathogenesis of Alzheimer’s disease

Zhou

et al. 2020

Preprint

View full text Add to dashboard Cite

Biochemical, pathogenic and human genetic data confirm that GSAP (γ-secretase activating protein), a selective γ-secretase modulatory protein, plays important roles in Alzheimer’s disease (AD) and Down syndrome. However, the molecular mechanism(s) underlying GSAP-dependent pathogenesis remains largely elusive. Here, through unbiased proteomics and single-nuclei RNA-seq, we identified that GSAP regulates multiple biological pathways, including protein phosphorylation, trafficking, lipid metabolism, and mitochondrial function. We demonstrated that GSAP physically interacts with Fe65:APP complex to regulate APP trafficking/partitioning. GSAP is enriched in the mitochondria-associated membrane (MAM) and regulates lipid homeostasis through the amyloidogenic processing of APP. GSAP deletion generates a lipid environment unfavorable for AD pathogenesis, leading to improved mitochondrial function and the rescue of cognitive deficits in an AD mouse model. Finally, we identified a novel GSAP single-nucleotide polymorphism that regulates its brain transcript level and is associated with an increased AD risk. Together, our findings indicate that GSAP impairs mitochondrial function through its MAM localization, and lowering GSAP expression reduces pathological effects associated with AD.

show abstract

“…The MSA FASTA files were processed on the T-Coffee server (Paolo et al 2011 ), and images were developed on the Boxshade v3.2 [ https://embnet.vital-it.ch/software/BOX_doc.html ] (ExPASy, 2019 ). The S-protein sequences were modeled on the locally installed Robetta (Walls et al 2020 ), model validation was performed by Qualitative model energy analysis (Qmean) and MolProbity method (Angira et al 2019 ). Ramachandran plot and images were generated in the Molecular Operating Environment (MOE) (Kerzare et al 2016 ).…”

Section: Methodsmentioning

confidence: 99%

Transmission of SARS-CoV-2 in South Asian countries: molecular evolutionary model based phylogenetic and mutation analysis

Maurya

Chikhale

Pandey

2020

Environmental Sustainability

View full text Add to dashboard Cite

The ongoing coronavirus disease 19 (COVID-19) pandemic has caused a very high number of infections and deaths around the globe. The absence of vaccine/drugs to counter COVID-19 has scrambled scientific communities to repurpose available medicines/vaccines. As the virus is known to mutate, using the whole genome sequences, the transmission dynamics and molecular evolutionary models were evaluated for South Asian countries to determine the evolutionary rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Phylogenetic analyses were done using the data available on National Center for Biotechnology Information (NCBI). Different nucleotide substitution models and molecular evolutionary models were analyzed to see how SARS-CoV-2 was transmitted in the populations. Models for the viral 'S' and 'N' protein from selected strains were constructed, validated, and analyzed to determine the mutations and discover the potential therapeutics against this deadly viral disease. We found that the Hasegawa-Kishino-Yano (HKY) nucleotide substitution model was the best model with the lowest Bayesian information criterion (BIC) scores. Molecular clock RelTime analysis showed the evolutionary rate of SARS-CoV-2 substitutions in the genome was at 95% confidence interval, and heterogeneity was observed. Several mutations in the viral S-protein were found with one in the receptor-binding domain concerning SARS-CoV-2/ Wuhan-1/S-Protein. Nucleocapsid protein also showed mutations in the strains from India and Sri Lanka. Our analysis suggests that SARS-CoV-2 is evolving at a diverse rate. The mutation leading to substitution in the nucleotide sequence occurred in the genome during the transmission of COVID-19 among individuals in the South Asian countries.

show abstract

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

Cited by 10 publications

References 56 publications

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

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

GSAP regulates mitochondrial function through the Mitochondria-associated ER membrane in the pathogenesis of Alzheimer’s disease

Transmission of SARS-CoV-2 in South Asian countries: molecular evolutionary model based phylogenetic and mutation analysis

Contact Info

Product

Resources

About