Probing Mechanisms and Therapeutic Potential of γ-Secretase in Alzheimer’s Disease

Wolfe, Michael S.

doi:10.3390/molecules26020388

Cited by 19 publications

(15 citation statements)

References 96 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Presenilin 1 and 2 (PS1, PS2) are two highly conserved, widely expressed, multipass transmembrane proteins mainly known as constituents of the catalytic core of the γ-secretase complex that is involved in the pathogenesis of Alzheimer's disease (AD). The high molecular weight aspartyl-protease complex is formed by either PS1 or PS2 (cleaved into the N-and C-terminal fragments, NTF and CTF, respectively) and three other additional proteins, anterior pharynx defective 1 (APH1), presenilin enhancer (PEN-2) and nicastrin [1,2]. The enzymatic complex catalyses endomembranous proteolysis of different type I membrane proteins, with Amyloid Precursor Protein (APP) being the most studied γ-secretase substrate because of its involvement in the formation of amyloid β (Aβ) peptides.…”

Section: Introductionmentioning

confidence: 99%

Loosening ER–Mitochondria Coupling by the Expression of the Presenilin 2 Loop Domain

Rossini

García-Casas

Filadi

et al. 2021

Cells

View full text Add to dashboard Cite

Presenilin 2 (PS2), one of the three proteins in which mutations are linked to familial Alzheimer’s disease (FAD), exerts different functions within the cell independently of being part of the γ-secretase complex, thus unrelated to toxic amyloid peptide formation. In particular, its enrichment in endoplasmic reticulum (ER) membrane domains close to mitochondria (i.e., mitochondria-associated membranes, MAM) enables PS2 to modulate multiple processes taking place on these signaling hubs, such as Ca2+ handling and lipid synthesis. Importantly, upregulated MAM function appears to be critical in AD pathogenesis. We previously showed that FAD-PS2 mutants reinforce ER–mitochondria tethering, by interfering with the activity of mitofusin 2, favoring their Ca2+ crosstalk. Here, we deepened the molecular mechanism underlying PS2 activity on ER–mitochondria tethering, identifying its protein loop as an essential domain to mediate the reinforced ER–mitochondria connection in FAD-PS2 models. Moreover, we introduced a novel tool, the PS2 loop domain targeted to the outer mitochondrial membrane, Mit-PS2-LOOP, that is able to counteract the activity of FAD-PS2 on organelle tethering, which possibly helps in recovering the FAD-PS2-associated cellular alterations linked to an increased organelle coupling.

show abstract

Section: Introductionmentioning

confidence: 99%

Loosening ER–Mitochondria Coupling by the Expression of the Presenilin 2 Loop Domain

Rossini

García-Casas

Filadi

et al. 2021

Cells

View full text Add to dashboard Cite

show abstract

“…γ-Secretase is a unique enzyme that has a separate substrate docking site and the active site [16,26,30]. In this study, we show that γ-secretase can bind in parallel different substrate molecules, at the docking site and the active site.…”

Section: Introductionmentioning

confidence: 75%

Binding of different substrate molecules at the docking site and the active site of γ-secretase can trigger toxic events in sporadic and familial Alzheimer’s disease

Svedružić

Šendula-Jengić

Ostojić

2022

Preprint

View full text Add to dashboard Cite

Significance: pathogenic changes in γ-secretase activity, and its response to different drugs, can be greatly affected by changes in saturation of γ-secretase with its substrate. The molecular mechanism is unclear. Results: multiscale molecular dynamics studies show that saturation of γ-secretase with its substrate can result in parallel binding of different substrate molecules at the docking site and the active site. C-terminal domain of the second substrate can bind at cytosolic end of presenilin subunit while γ-secretase is still processing its first substrate. Such interactions can disrupt dynamic presenilin structures that regulate proteolytic steps. Similar disruptions in dynamic presenilin structures can be produced by different drugs and by different disease-causing mutations. Thus, the presented two-substrate mechanism, can explain toxic inhibition of γ-secretase activity and toxic increase in production of the longer, more hydrophobic, Aβ-proteins. Toxic aggregation between N-terminal domains of the two substrates is controlled by nicastrin ectodomain. Such aggregation is more likely to happen with C99-βCTF-APP than with C83-αCTF-APP substrate, which can explain, why β-secretase path is more pathogenic than α-secretase path. The binding of C99-βCTF-APP substrate to γ-secretase can be controlled by substrate-channeling between nicastrin ectodomain and β-secretase. Conclusions: The presented two-substrate mechanism can explain why different studies consistently show that increase in saturation of γ-secretase with its substrate can support pathogenic changes in different sporadic and familiar cases of the disease. Future drug-development strategies can target different physiological mechanisms that control the balance between cellular levels of γ-secretase activity and the total amyloid metabolism.

show abstract

“…These results are relevant not only to understanding the pathogenesis of AD, but also to the development of AD therapeutics. As modulation of g-secretase activity is increasingly being proposed as a promising route to AD therapeutics, [72][73][74] an understanding of how different Ab alloforms-and how different combinations of these alloforms-affect pathological Ab 42 aggregation is becoming increasingly important.…”

Section: Discussionmentioning

confidence: 99%

Amyloid-β peptide 37, 38 and 40 individually and cooperatively inhibit amyloid-β 42 aggregation

et al. 2022

View full text Add to dashboard Cite

show abstract

Probing Mechanisms and Therapeutic Potential of γ-Secretase in Alzheimer’s Disease

Cited by 19 publications

References 96 publications

Loosening ER–Mitochondria Coupling by the Expression of the Presenilin 2 Loop Domain

Loosening ER–Mitochondria Coupling by the Expression of the Presenilin 2 Loop Domain

Binding of different substrate molecules at the docking site and the active site of γ-secretase can trigger toxic events in sporadic and familial Alzheimer’s disease

Amyloid-β peptide 37, 38 and 40 individually and cooperatively inhibit amyloid-β 42 aggregation

Contact Info

Product

Resources

About