scholarly journals Specific Mutations in Aph1 Cause γ-Secretase Activation

2022 ◽  
Vol 23 (1) ◽  
pp. 507
Author(s):  
Hikari Watanabe ◽  
Chika Yoshida ◽  
Masafumi Hidaka ◽  
Tomohisa Ogawa ◽  
Taisuke Tomita ◽  
...  
Keyword(s):  
Opposite Effect ◽  
Regulatory Subunit ◽  
Regulatory Function ◽  
Loss Of Function ◽  
Embryonic Fibroblasts ◽  
Amyloid Beta Peptides ◽  
Activating Mutations ◽  
Beta Peptides ◽  
Secretase Activity ◽  
Aβ Production

Amyloid beta peptides (Aβs) are generated from amyloid precursor protein (APP) through multiple cleavage steps mediated by γ-secretase, including endoproteolysis and carboxypeptidase-like trimming. The generation of neurotoxic Aβ42/43 species is enhanced by familial Alzheimer’s disease (FAD) mutations within the catalytic subunit of γ-secretase, presenilin 1 (PS1). FAD mutations of PS1 cause partial loss-of-function and decrease the cleavage activity. Activating mutations, which have the opposite effect of FAD mutations, are important for studying Aβ production. Aph1 is a regulatory subunit of γ-secretase; it is presumed to function as a scaffold of the complex. In this study, we identified Aph1 mutations that are active in the absence of nicastrin (NCT) using a yeast γ-secretase assay. We analyzed these Aph1 mutations in the presence of NCT; we found that the L30F/T164A mutation is activating. When introduced in mouse embryonic fibroblasts, the mutation enhanced cleavage. The Aph1 mutants produced more short and long Aβs than did the wild-type Aph1, without an apparent modulatory function. The mutants did not change the amount of γ-secretase complex, suggesting that L30F/T164A enhances catalytic activity. Our results provide insights into the regulatory function of Aph1 in γ-secretase activity.

The Regulatory Function of the Molecular Chaperone Hsp90 in the Cell Wall Integrity of Pathogenic Fungi

2018 ◽  
Vol 16 (1) ◽  
pp. 44-53
Author(s):  
Marina Campos Rocha ◽  
Camilla Alves Santos ◽  
Iran Malavazi
Keyword(s):  
Cell Wall ◽  
Antifungal Therapy ◽  
Molecular Chaperone ◽  
Regulatory Protein ◽  
Pathogenic Fungi ◽  
Antifungal Drugs ◽  
Cell Wall Integrity ◽  
Regulatory Function ◽  
Loss Of Function ◽  
Hsp90 Inhibition

Different signaling cascades including the Cell Wall Integrity (CWI), the High Osmolarity Glycerol (HOG) and the Ca2+/calcineurin pathways control the cell wall biosynthesis and remodeling in fungi. Pathogenic fungi, such as Aspergillus fumigatus and Candida albicans, greatly rely on these signaling circuits to cope with different sources of stress, including the cell wall stress evoked by antifungal drugs and the host’s response during infection. Hsp90 has been proposed as an important regulatory protein and an attractive target for antifungal therapy since it stabilizes major effector proteins that act in the CWI, HOG and Ca2+/calcineurin pathways. Data from the human pathogen C. albicans have provided solid evidence that loss-of-function of Hsp90 impairs the evolution of resistance to azoles and echinocandin drugs. In A. fumigatus, Hsp90 is also required for cell wall integrity maintenance, reinforcing a coordinated function of the CWI pathway and this essential molecular chaperone. In this review, we focus on the current information about how Hsp90 impacts the aforementioned signaling pathways and consequently the homeostasis and maintenance of the cell wall, highlighting this cellular event as a key mechanism underlying antifungal therapy based on Hsp90 inhibition.

scholarly journals ATP13A2 Regulates Cellular α-Synuclein Multimerization, Membrane Association, and Externalization

2021 ◽  
Vol 22 (5) ◽  
pp. 2689
Author(s):  
Jianmin Si ◽  
Chris Van den Haute ◽  
Evy Lobbestael ◽  
Shaun Martin ◽  
Sarah van Veen ◽  
...  
Keyword(s):  
Membrane Integrity ◽  
Ubiquitin Proteasome System ◽  
Regulatory Function ◽  
Membrane Association ◽  
Loss Of Function ◽  
Atypical Form ◽  
Polyamine Transport ◽  
Independent Functions ◽  
Ubiquitin Proteasome ◽  
The Impact

ATP13A2, a late endo-/lysosomal polyamine transporter, is implicated in a variety of neurodegenerative diseases, including Parkinson’s disease and Kufor–Rakeb syndrome, an early-onset atypical form of parkinsonism. Loss-of-function mutations in ATP13A2 result in lysosomal deficiency as a consequence of impaired lysosomal export of the polyamines spermine/spermidine. Furthermore, accumulating evidence suggests the involvement of ATP13A2 in regulating the fate of α-synuclein, such as cytoplasmic accumulation and external release. However, no consensus has yet been reached on the mechanisms underlying these effects. Here, we aimed to gain more insight into how ATP13A2 is linked to α-synuclein biology in cell models with modified ATP13A2 activity. We found that loss of ATP13A2 impairs lysosomal membrane integrity and induces α-synuclein multimerization at the membrane, which is enhanced in conditions of oxidative stress or exposure to spermine. In contrast, overexpression of ATP13A2 wildtype (WT) had a protective effect on α-synuclein multimerization, which corresponded with reduced αsyn membrane association and stimulation of the ubiquitin-proteasome system. We also found that ATP13A2 promoted the secretion of α-synuclein through nanovesicles. Interestingly, the catalytically inactive ATP13A2 D508N mutant also affected polyubiquitination and externalization of α-synuclein multimers, suggesting a regulatory function independent of the ATPase and transport activity. In conclusion, our study demonstrates the impact of ATP13A2 on α-synuclein multimerization via polyamine transport dependent and independent functions.

Selective Secretase Targeting for Alzheimer’s Disease Therapy

2021 ◽  
pp. 1-17
Author(s):  
Alvaro Miranda ◽  
Enrique Montiel ◽  
Henning Ulrich ◽  
Cristian Paz
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Neuroprotective Activity ◽  
Amyloid Β Protein ◽  
Secretase Activity ◽  
Membrane Bound ◽  
Aβ Production ◽  
Bace 1

Alzheimer’s disease (AD) is associated with marked atrophy of the cerebral cortex and accumulation of amyloid plaques and neurofibrillary tangles. Amyloid plaques are formed by oligomers of amyloid-β (Aβ) in the brain, with a length of 42 and 40 amino acids. α-secretase cleaves amyloid-β protein precursor (AβPP) producing the membrane-bound fragment CTFα and the soluble fragment sAβPPα with neuroprotective activity; β-secretase produces membrane-bound fragment CTFβ and a soluble fragment sAβPPβ. After α-secretase cleavage of AβPP, γ-secretase cleaves CTFα to produce the cytoplasmic fragment AICD and P3 in the non-amyloidogenic pathway. CTFβ is cleaved by γ-secretase producing AICD as well as Aβ in amyloidogenic pathways. In the last years, the study of natural products and synthetic compounds, such as α-secretase activity enhancers, β-secretase inhibitors (BACE-1), and γ-secretase activity modulators, have been the focus of pharmaceuticals and researchers. Drugs were improved regarding solubility, blood-brain barrier penetration, selectivity, and potency decreasing Aβ42. In this regard, BACE-1 inhibitors, such as Atabecestat, NB-360, Umibecestat, PF-06751979, Verubecestat, LY2886721, Lanabecestat, LY2811376, and Elenbecestat, were submitted to phase I-III clinical trials. However, inhibition of Aβ production did not recover cognitive functions or reverse the disease. Novel strategies are being developed, aiming at a partial reduction of Aβ production, such as the development of γ-secretase modulators or α-secretase enhancers. Such therapeutic tools shall focus on slowing down or minimizing the progression of neuronal damage. Here, we summarize structures and the activities of the latest compounds designed for AD treatment, with remarkable in vitro, in vivo, and clinical phase activities.

Amyloid beta peptides and glutamatergic synaptic dysregulation

2008 ◽  
Vol 210 (1) ◽  
pp. 7-13 ◽  
Author(s):  
Kodeeswaran Parameshwaran ◽  
Muralikrishnan Dhanasekaran ◽  
Vishnu Suppiramaniam
Keyword(s):  
Amyloid Beta ◽  
Amyloid Beta Peptides ◽  
Beta Peptides

scholarly journals The Ubiquitously Expressed Csk Adaptor Protein Cbp Is Dispensable for Embryogenesis and T-Cell Development and Function

2005 ◽  
Vol 25 (23) ◽  
pp. 10533-10542 ◽  
Author(s):  
Marc-Werner Dobenecker ◽  
Christian Schmedt ◽  
Masato Okada ◽  
Alexander Tarakhovsky
Keyword(s):  
T Cell ◽  
Adaptor Protein ◽  
Regulatory Function ◽  
Loss Of Function ◽  
Thymic Development ◽  
Cell Functions ◽  
Carboxy Terminal ◽  
And Function

ABSTRACT Regulation of Src family kinase (SFK) activity is indispensable for a functional immune system and embryogenesis. The activity of SFKs is inhibited by the presence of the carboxy-terminal Src kinase (Csk) at the cell membrane. Thus, recruitment of cytosolic Csk to the membrane-associated SFKs is crucial for its regulatory function. Previous studies utilizing in vitro and transgenic models suggested that the Csk-binding protein (Cbp), also known as phosphoprotein associated with glycosphingolipid microdomains (PAG), is the membrane adaptor for Csk. However, loss-of-function genetic evidence to support this notion was lacking. Herein, we demonstrate that the targeted disruption of the cbp gene in mice has no effect on embryogenesis, thymic development, or T-cell functions in vivo. Moreover, recruitment of Csk to the specialized membrane compartment of “lipid rafts” is not impaired by Cbp deficiency. Our results indicate that Cbp is dispensable for the recruitment of Csk to the membrane and that another Csk adaptor, yet to be discovered, compensates for the loss of Cbp.

Deferoxamine reduces amyloid-beta peptides genesis and alleviates neural apoptosis after traumatic brain injury

Neuroreport ◽  
2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Wang-Dui Zhaba ◽  
Qu-Zhen Deji ◽  
Sheng-Qing Gao ◽  
Yan-Ling Han ◽  
Chao-Chao Gao ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Amyloid Beta ◽  
Amyloid Beta Peptides ◽  
Beta Peptides ◽  
Neural Apoptosis

scholarly journals Intracellular APP Domain Regulates Serine-Palmitoyl-CoA Transferase Expression and Is Affected in Alzheimer's Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Marcus O. W. Grimm ◽  
Sven Grösgen ◽  
Tatjana L. Rothhaar ◽  
Verena K. Burg ◽  
Benjamin Hundsdörfer ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
De Novo ◽  
Physiological Function ◽  
Proteolytic Processing ◽  
Sphingolipid Metabolism ◽  
Amyloid Beta Peptides ◽  
Beta Peptides ◽  
Coa Transferase ◽  
Key Enzyme

Lipids play an important role as risk or protective factors in Alzheimer's disease (AD), a disease biochemically characterized by the accumulation of amyloid beta peptides (Aβ), released by proteolytic processing of the amyloid precursor protein (APP). Changes in sphingolipid metabolism have been associated to the development of AD. The key enzyme in sphingolipidde novosynthesis is serine-palmitoyl-CoA transferase (SPT). In the present study we identified a new physiological function of APP in sphingolipid synthesis. The APP intracellular domain (AICD) was found to decrease the expression of the SPT subunit SPTLC2, the catalytic subunit of the SPT heterodimer, resulting in that decreased SPT activity. AICD function was dependent on Fe65 and SPTLC2 levels are increased in APP knock-in mice missing a functional AICD domain. SPTLC2 levels are also increased in familial and sporadic ADpostmortembrains, suggesting that SPT is involved in AD pathology.

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