Article
Biochemistry & Molecular Biology
Meewhi Kim, Ilya Bezprozvanny
Summary: Proteolytic processing of amyloid precursor protein (APP) is critical in the pathogenesis of Alzheimer's disease (AD). Mutations in APP, PS1, or PS2 affect APP proteolysis by gamma-secretase and influence the levels of A beta 40 and A beta 42 peptides. This paper proposes a mechanistic hypothesis that may reconcile conflicting ideas and observations regarding the role of A beta peptides and gamma-secretase in AD.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Hematology
Irene Cattaneo, Rut Valgardsdottir, Roberta Cavagna, Orietta Spinelli, Anna Bartoletti-Stella, Sabina Capellari, Monica Galli, Josee Golay
Summary: This study revealed that MM cells from one patient exhibited high and dysregulated BCMA expression, which was not regulated by gamma-secretase inhibitor. Genetic analysis showed that there were no mutations in the BCMA coding region, but partial deletion of PSEN1 and amplification of PSEN2, indicating genetic alterations in the gamma-secretase subunits.
BRITISH JOURNAL OF HAEMATOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Congkuan Song, Jinjin Zhang, Chenzhen Xu, Minglang Gao, Ning Li, Qing Geng
Summary: This article discusses the potential and problems of gamma-secretase and its inhibitors in cancer treatment, introducing gamma-secretase as a multi-substrate enzyme and its important role in cellular activities. The failure of current GSIs in clinical trials may be attributed to various factors.
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
(2023)
Editorial Material
Biochemistry & Molecular Biology
Daniel R. Dries, Gang Yu
Summary: Research showed that gamma-secretase is a potential therapeutic target for Alzheimer's disease, and provided new opportunities for treatment.
Article
Dermatology
S. Vural, M. Baumgartner, P. Lichtner, G. Eckstein, H. Hariry, W. C. Chen, T. Ruzicka, B. Melnik, G. Plewig, M. Wagner, K. A. Giehl
Summary: Hidradenitis suppurativa (HS) is a chronic inflammatory disease affecting apocrine gland-bearing skin, with some cases showing mutations in the gamma secretase gene complex. The genetic basis of HS was investigated in this study by sequencing genes encoding the gamma secretase complex and performing genetic mapping with parametric linkage analysis. Results suggest rare mutations in the gamma secretase gene complex in HS patients, and a possible complex multi-genic inheritance in a multi-generational HS family.
JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Matthias Koch, Thomas Enzlein, Shu-Yu Chen, Dieter Petit, Sam Lismont, Martin Zacharias, Carsten Hopf, Lucia Chavez-Gutierrez
Summary: This study explores the mechanism that controls the processing of the amyloid precursor protein (APP) by gamma-secretases, which is crucial in determining the length of amyloid-beta (A beta) peptides and their role in Alzheimer's disease (AD) pathogenesis. The researchers found that polar interactions established by the APPC99 ectodomain (ECD) play a key role in regulating the cleavage of APP by gamma-secretases. Increasing the hydrophobicity of APPC99-ECD attenuates substrate-driven product release and rescues the effects of Alzheimer's disease-associated pathogenic gamma-secretase and APP variants on A beta length. Furthermore, the study reveals that APPC99-ECD facilitates the production of longer A beta peptides caused by certain gamma-secretase inhibitors. These findings highlight the importance of the APPC99-ECD in regulating gamma-secretase activity and suggest it as a potential target for developing compounds that can selectively promote APP processing by these enzymes.
Article
Neurosciences
Sofia Essayan-Perez, Thomas C. Sudhof
Summary: Chronic suppression of γ-secretase increases synapse numbers but decreases synaptic transmission, and this impairment is caused by the lowered cholesterol levels.
Review
Genetics & Heredity
Nikolai Paul Pace, Dillon Mintoff, Isabella Borg
Summary: This review provides a comprehensive overview of the role of genetics in various aspects of hidradenitis suppurativa, including pathophysiology, diagnosis, and clinical application.
FRONTIERS IN GENETICS
(2022)
Article
Biochemistry & Molecular Biology
Prasoon Agarwal, Aleksandra Glowacka, Loay Mahmoud, Wesam Bazzar, Lars-Gunnar Larsson, Mohammad Alzrigat
Summary: Amplification of the MYCN oncogene in neuroblastoma is associated with high-risk disease and poor prognosis. This study reveals that MYCN-amplified neuroblastoma cells have reduced expression of genes involved in NOTCH receptor processing, axoneme assembly, and membrane protein proteolysis. Genes encoding gamma-secretase complex subunits, known for their role in NOTCH signaling, are down-regulated in MYCN-amplified neuroblastoma. Depletion of MYCN or inhibition of gamma-secretase activity restores the expression of gamma-secretase and NOTCH-target genes. This study provides insight into the molecular mechanisms underlying MYCN's contribution to high-risk neuroblastoma.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Urszula Orzel, Jakub Jakowiecki, Krzysztof Mlynarczyk, Slawomir Filipek
Summary: The study showed that at high cholesterol levels, Aβ(45) was more flexible in the binding site of presenilin than Aβ(43), but the active site of presenilin at the C-terminal part of Aβ(45) was more compact, which could promote processing of this substrate. Cholesterol binding sites at low and high concentrations were also mapped, independent of typical cholesterol binding motifs.
Article
Genetics & Heredity
Dillon Mintoff, Nikolai P. Pace, Isabella Borg
Summary: Hidradenitis suppurativa (HS) is a complex disease of the pilosebaceous unit characterized by inflammation and hyperkeratinization at the hair follicle playing crucial roles. Genetic and environmental factors may be the main drivers of these processes. Studying the burden of genomic variations in GSC protein-coding genes in the patient cohort helps to provide a standard for comparison.
FRONTIERS IN GENETICS
(2022)
Article
Oncology
Tyler R. McCaw, Evelyn Inga, Herbert Chen, Renata Jaskula-Sztul, Vikas Dudeja, James A. Bibb, Bin Ren, J. Bart Rose
Summary: Gamma secretase inhibitors (GSIs), originally developed as Alzheimer's therapies, have been repurposed as anticancer agents due to their ability to inhibit Notch receptor cleavage. Despite showing promise in preclinical models, GSIs have not demonstrated significant clinical benefit in most solid tumors. Further research is needed to address limitations in understanding GSI mechanisms and improve their efficacy in cancer treatment.
Review
Neurosciences
Gunnar Nordvall, Johan Lundkvist, Johan Sandin
Summary: Recent clinical data have shown that removing A beta-amyloid plaques in early Alzheimer's disease can slow down disease progression. This progress validates the amyloid cascade hypothesis and highlights the importance of targeting A beta-amyloid for therapeutic purposes. It also suggests that reducing the production of amyloidogenic A beta can prevent the formation of A beta-pathology. Further research is needed to explore the potential of gamma-secretase modulators in preventing and treating Alzheimer's disease.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2023)
Article
Multidisciplinary Sciences
Whendy Contreras, Caroline Wiesehofer, Dora Schreier, Nadja Leinung, Petra Peche, Gunther Wennemuth, Marc Gentzel, Bernd Schroder, Torben Mentrup
Summary: This study provides a detailed characterization of the C11orf94 protein, renamed as Frey, which plays a crucial role in the assembly of Izumo1 complexes. By retaining Izumo1 in the endoplasmic reticulum, Frey facilitates its incorporation into high molecular weight complexes.
Article
Biochemistry & Molecular Biology
Dieter Petit, Manuel Hitzenberger, Matthias Koch, Sam Lismont, Katarzyna Marta Zoltowska, Thomas Enzlein, Carsten Hopf, Martin Zacharias, Lucia Chavez-Gutierrez
Summary: This study investigates the interactions between an imidazole-based GSM and its target gamma-secretase-APP, and reveals that a part of the modulator interacts with a binding site on gamma-secretase, triggering rearrangements and stabilizing enzyme-substrate interactions.
Article
Neurosciences
Macarena Pavez, Adrian C. Thompson, Hayden J. Arnott, Camilla B. Mitchell, Ilaria D'Atri, Emily K. Don, John K. Chilton, Ethan K. Scott, John Y. Lin, Kaylene M. Young, Robert J. Gasperini, Lisa Foa
JOURNAL OF NEUROSCIENCE
(2019)
Article
Environmental Sciences
Santon Thayer, Ellen J. Bennett, Lisa Foa, Stephen M. Richards, A. Bruce Lyons, Graeme R. Zosky
Article
Neurosciences
Kimberley A. Pitman, Raphael Ricci, Robert Gasperini, Shannon Beasley, Macarena Pavez, Jac Charlesworth, Lisa Foa, Kaylene M. Young
Article
Biochemistry & Molecular Biology
Silvia Vicenzi, Lisa Foa, Robert J. Gasperini
Summary: The neurotransmitter serotonin can act as both an attractive and repulsive guidance cue for rodent sensory neurons in vitro, with extracellular gradients of 50 mu M serotonin inducing attraction mediated by the serotonin 5-HT2a receptor and 100 mu M serotonin inducing repulsion mediated by the 5-HT1b receptor. High resolution imaging of growth cones showed that these receptors signal through their canonical pathways to shape neuronal circuit formation during development.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Article
Environmental Sciences
Santon Thaver, Lisa Foa, Stephen M. Richards, A. Bruce Lyons, Graeme R. Zosky
Summary: In utero exposure to particulate matter from different sources affects post-natal immune development and function, with the response varying depending on the PM source. Diesel exhaust particles had different effects on male and female mice, while exposure to silica had no impact on the measured immune parameters.
Article
Environmental Sciences
Yong Song, Katherine Southam, Ellen Bennett, Fay Johnston, Lisa Foa, Amanda J. Wheeler, Graeme R. Zosky
Summary: The study found that gestational exposure to residential roof space PM during pregnancy affects body weight and brain development in post-natal mice, particularly leading to increased myelin load in the white matter and elevated microglial density.
ENVIRONMENTAL RESEARCH
(2021)
Article
Neurosciences
Katherine Southam, Chantal de Sousa, Abraham Daniel, Bruce Taylor, Lisa Foa, Dino Premilovac
Summary: Accurate modeling of type 2 diabetes and its complications in rodents is a challenge. In this study, a new rodent model of type 2 diabetes was developed using a high fat/high sugar diet and streptozotocin infusion. The model successfully induced different stages of type 2 diabetes and exhibited metabolic dysfunction and peripheral neurodegeneration, making it a valuable tool for studying the pathophysiological mechanisms underlying diabetic complications.
JOURNAL OF PHYSIOLOGY-LONDON
(2022)
Article
Cell Biology
Lachlan S. Brown, Natalie E. King, Jo-Maree Courtney, Robert J. Gasperini, Lisa Foa, David W. Howells, Brad A. Sutherland
Summary: Pericytes in the neurovascular unit have multiple important functions, but their heterogeneity has not been well considered in previous studies. By using primary human brain vascular pericytes (HBVP) cultures, researchers identified five distinct morphological subtypes. These subtypes displayed different behaviors and expression of contractility-related protein. Understanding pericyte heterogeneity is crucial for accurately modeling their physiology in vitro.
CELL BIOLOGY AND TOXICOLOGY
(2023)
Article
Cell Biology
Loic Auderset, Kimberley A. Pitman, Carlie L. Cullen, Renee E. Pepper, Bruce V. Taylor, Lisa Foa, Kaylene M. Young
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2020)
Meeting Abstract
Neurosciences
R. P. Ricci, K. A. Pitman, R. Gasperini, J. Charlesworth, L. Foa, K. M. Young
Meeting Abstract
Critical Care Medicine
S. Thaver, E. Bennett, L. Foa, S. Richards, B. Lyons, G. R. Zosky
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
(2019)
Meeting Abstract
Respiratory System
S. Thaver, E. Bennett, L. Foa, S. Richards, B. Lyons, G. Zosky
Meeting Abstract
Critical Care Medicine
G. R. Zosky, S. Thaver, E. Bennett, L. Foa, S. Richards, B. Lyons
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
(2018)
Meeting Abstract
Respiratory System
S. Thaver, E. Bennett, L. Foa, S. Richards, B. Lyons, G. Zosky
Meeting Abstract
Clinical Neurology
Kaylene Young, Yilan Zhen, Robert Gasperini, Carlie Cullen, Dominic Cosgrove, Lisa Foa
MULTIPLE SCLEROSIS JOURNAL
(2017)
