Protein Phosphatase 2A (PP2A) mutations in brain function, development, and neurologic disease

By removing Ser/Thr-specific phosphorylations in a multitude of protein substrates in diverse tissues, Protein Phosphatase type 2A (PP2A) enzymes play essential regulatory roles in cellular signalling and physiology, including in brain function and development. Here, we review current knowledge on PP2A gene mutations causally involved in neurodevelopmental disorders and intellectual disability, focusing on PPP2CA, PPP2R1A and PPP2R5D. We provide insights into the impact of these mutations on PP2A structure, substrate specificity and potential function in neurobiology and brain development.

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HYPOXIA AND REPRODUCTIVE HEALTH: The presence and role of hypoxia in the endometrium

Reproduction ◽

10.1530/rep-20-0268 ◽

2021 ◽

Vol 161 (1) ◽

pp. F1-F17

Author(s):

Rocío Martínez-Aguilar ◽

Lucy E Kershaw ◽

Jane J Reavey ◽

Hilary O D Critchley ◽

Jacqueline A Maybin

Keyword(s):

Current Knowledge ◽

Abnormal Uterine Bleeding ◽

Future Research ◽

Hypoxic Episode ◽

Optimal Function ◽

Pros And Cons ◽

The Impact ◽

Review Current

The endometrium is a multicellular tissue that is exquisitely responsive to the ovarian hormones. The local mechanisms of endometrial regulation to ensure optimal function are less well characterised. Transient physiological hypoxia has been proposed as a critical regulator of endometrial function. Herein, we review the literature on hypoxia in the non-pregnant endometrium. We discuss the pros and cons of animal models, human laboratory studies and novel in vivo imaging for the study of endometrial hypoxia. These research tools provide mounting evidence of a transient hypoxic episode in the menstrual endometrium and suggest that endometrial hypoxia may be present at the time of implantation. This local hypoxia may modify the inflammatory environment, influence vascular remodelling and modulate endometrial proliferation to optimise endometrial function. Finally, we review current knowledge of the impact of this hypoxia on endometrial pathologies, with a focus on abnormal uterine bleeding. Throughout the manuscript areas for future research are highlighted with the aim of concentrating research efforts to maximise future benefits for women and society.

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Sepsis: Precision-Based Medicine for Pregnancy and the Puerperium

International Journal of Molecular Sciences ◽

10.3390/ijms20215388 ◽

2019 ◽

Vol 20 (21) ◽

pp. 5388

Author(s):

Orene Greer ◽

Nishel Mohan Shah ◽

Shiranee Sriskandan ◽

Mark R. Johnson

Keyword(s):

Pregnant Women ◽

Current Knowledge ◽

Rapid Progression ◽

Therapeutic Approaches ◽

Maternal Deaths ◽

Neonatal Deaths ◽

Sepsis And Septic Shock ◽

Based Medicine ◽

The Impact ◽

Review Current

Sepsis contributes significantly to global morbidity and mortality, particularly in vulnerable populations. Pregnant and recently pregnant women are particularly prone to rapid progression to sepsis and septic shock, with 11% of maternal deaths worldwide being attributed to sepsis. The impact on the neonate is considerable, with 1 million neonatal deaths annually attributed to maternal infection or sepsis. Pregnancy specific physiological and immunological adaptations are likely to contribute to a greater impact of infection, but current approaches to the management of sepsis are based on those developed for the non-pregnant population. Pregnancy-specific strategies are required to optimise recognition and management of these patients. We review current knowledge of the physiology and immunology of pregnancy and propose areas of research, which may advance the development of pregnancy-specific diagnostic and therapeutic approaches to optimise the care of pregnant women and their babies.

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Molecular Mechanisms Underlying the Beneficial Effects of Exercise on Brain Function and Neurological Disorders

International Journal of Molecular Sciences ◽

10.3390/ijms22084052 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4052

Author(s):

Kévin Nay ◽

William J. Smiles ◽

Jacqueline Kaiser ◽

Luke M. McAloon ◽

Kim Loh ◽

...

Keyword(s):

Brain Function ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Well Being ◽

Developed Countries ◽

Beneficial Effects ◽

Therapeutic Benefits ◽

Age Related ◽

Underlying Mechanisms ◽

The Impact

As life expectancy has increased, particularly in developed countries, due to medical advances and increased prosperity, age-related neurological diseases and mental health disorders have become more prevalent health issues, reducing the well-being and quality of life of sufferers and their families. In recent decades, due to reduced work-related levels of physical activity, and key research insights, prescribing adequate exercise has become an innovative strategy to prevent or delay the onset of these pathologies and has been demonstrated to have therapeutic benefits when used as a sole or combination treatment. Recent evidence suggests that the beneficial effects of exercise on the brain are related to several underlying mechanisms related to muscle–brain, liver–brain and gut–brain crosstalk. Therefore, this review aims to summarize the most relevant current knowledge of the impact of exercise on mood disorders and neurodegenerative diseases, and to highlight the established and potential underlying mechanisms involved in exercise–brain communication and their benefits for physiology and brain function.

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Contribution of cell proliferation possibly due to inactivation of protein phosphatase 2A to gene mutations induced by estragole

Toxicology Letters ◽

10.1016/j.toxlet.2015.08.719 ◽

2015 ◽

Vol 238 (2) ◽

pp. S244

Author(s):

Y. Ishii ◽

K. Kuroda ◽

S. Takasu ◽

Y. Yokoo ◽

T. Tsuchiya ◽

...

Keyword(s):

Cell Proliferation ◽

Protein Phosphatase ◽

Protein Phosphatase 2A ◽

Gene Mutations ◽

Phosphatase 2A

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Protein phosphatase 2A activation attenuates inflammation in murine models of acute lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00007.2016 ◽

2016 ◽

Vol 311 (5) ◽

pp. L903-L912 ◽

Cited By ~ 5

Author(s):

Walker M. McHugh ◽

William W. Russell ◽

Andrew J. Fleszar ◽

Paul E. Rodenhouse ◽

Skyler P. Rietberg ◽

...

Keyword(s):

Lung Injury ◽

Protein Phosphatase ◽

Protein Phosphatase 2A ◽

Neutrophil Infiltration ◽

Neutrophil Recruitment ◽

Bacterial Challenge ◽

Chemokine Production ◽

Pp2a Activity ◽

Phosphatase 2A ◽

The Impact

Acute respiratory distress syndrome (ARDS) remains a leading cause of morbidity and mortality in both adult and pediatric intensive care units. A key event in the development of ARDS is neutrophil recruitment into the lungs leading to tissue damage and destruction. Interleukin-8 (IL-8) is the major human chemokine responsible for neutrophil recruitment into the lungs. Protein phosphatase 2A (PP2A) has been shown to be a key regulator of the mitogen-activated protein kinase (MAPK) cascades, which control the production of IL-8. Previously, our laboratory employed an in vitro model to show that inhibition of PP2A results in an increase in IL-8 production in human alveolar epithelial cells. The objective of this study was to determine whether PP2A regulated this response in vivo by investigating the impact of pharmacologic activation of PP2A on chemokine production and activation of the MAPK cascade and lung injury using endotoxin- and bacterial-challenge models of ARDS in mice. N6-cyclopentyladenosine ( N6-CPA) increased PP2A activity and inhibited endotoxin-induced cytokine production in a murine alveolar macrophage cell line. N6-CPA pretreatment in mice challenged with intratracheal endotoxin decreased chemokine production, reduced neutrophil infiltration, and attenuated lung injury. Following initiation of lung injury with live Pseudomonas aeruginosa, mice that received N6-CPA 4 h following bacterial challenge showed attenuated chemokine production and reduced neutrophil infiltration compared with control mice. Pharmacologic PP2A activation both limited and prevented inflammation and tissue injury in two direct injury models of ARDS. These results suggest modulation of PP2A activity as a therapeutic target in ARDS.

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