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F1000Res,
2016]
Since its first description in 1968, IgA nephropathy has remained the most common form of primary glomerulonephritis leading to chronic kidney disease in developed countries. The clinical progression varies, and consequent end-stage renal disease occurs in 30% to 40% of patients 20 to 30 years after the first clinical presentation. Current data implicate overproduction of aberrantly glycosylated IgA1 as being pivotal in the induction of renal injury. Effective and specific treatment is still lacking, and new therapeutic approaches will be developed after better understanding the disease pathogenesis.
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Trends Cell Biol,
2010]
A wealth of evidence underscores the tight link between oxidative stress, neurodegeneration and aging. When the level of excess reactive oxygen species (ROS) increases in the cell, a phenomenon characteristic of aging, DNA is damaged, proteins are oxidized, lipids are degraded and more ROS are produced, all culminating in significant cell injury. Recently we showed that in the nematode, Caenorhabditis elegans, oxidation of K(+) channels by ROS is a major mechanism underlying the loss of neuronal function. The C. elegans results support an argument that K(+) channels controlling neuronal excitability and survival might provide a common, functionally important substrate for ROS in aging mammals. Here we discuss the implications that oxidation of K(+) channels by ROS might have for the mammalian brain during normal aging, as well as in neurodegenerative diseases such as Alzheimer's and Parkinson's. We argue that oxidation of K(+) channels by ROS is a common theme in the aging brain and suggest directions for future experimentation.
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Physiology (Bethesda),
2009]
Recent work shows that transport-independent as well as transport-dependent functions of ion transporters, and in particular the Na-K-ATPase, are required for formation and maintenance of several intercellular junctions. Furthermore, these junctional and other nonjunctional functions of ion transporters contribute to development of epithelial tubes. Here, we consider what has been learned about the roles of ion pumps in formation of junctions and epithelial tubes in mammals, zebrafish, Drosophila, and C. elegans. We propose that asymmetric association of the Na-K-ATPase with cell junctions early in metazoan evolution enabled vectorial transcellular ion transport and control of intraorganismal environment. Ion transport-independent functions of the Na-K-ATPase arose as junctional complexes evolved.
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Exp Gerontol,
2013]
This communication will briefly review more than 30 years of research on aging using the nematode Caenorhabditis elegans ("The Worm") as carried out in the labs of Tom Johnson. We will highlight research directions initiated in the 1980's, which were exciting for those of us trying to turn over a new leaf in aging research. In this narrative, I will discuss primarily the science that I and my lab have been involved with for the last 30 years. This area has been fascinating to those studying the sociology of science as modern aging research has moved to replace the simplistic, poorly controlled and outright fictitious approaches seen in much of the previous aging research.
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Trends in Pharmacological Sciences,
2005]
K+ channels that possess two pore domains in each channel subunit are common in many animal tissues. Such channels are generated from large families of subunits and are implicated in several functions, including temperature sensation, responses to ischaemia, K+ homeostasis and setting the resting potential of the cell. Their activity can be modulated by polyunsaturated fatty acids, pH and oxygen, and some are candidate targets of volatile anaesthetics. However, despite their potential as targets for novel drugs for human health, comparatively little is known about the molecular basis of their diverse physiological and pharmacological properties. Genetic model organisms have considerable potential for improving our understanding of these channels. In this article, we review the contributions of some of these genetic model organisms to recent advances in our knowledge of two-pore-domain K+
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Nature Cell Biology,
1999]
Studies on the role of cholesterol- and caveolin-rich membrane microdomains in localizing Ras to the plasma membrane and enabling its signalling activity reveal intriguing differences both between mammalian H-Ras and K-Ras and between requirements for Ras signalling in mammalian and nematode cells.
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Trends in Genetics,
1987]
Tc1 is a 1.6 kbp DNA sequence present in about 30 copies in some strains of C. elegans and 300 or more copies in other strains. Tc1 elements excise much more frequently in somatic cells than in the germ line. Germ-line transposition of Tc1 has been detected and is under genetic control. Tc1 has become very useful as a tool for cloning C. elegans genes identified soley by mutation.
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Biochim Biophys Acta,
2010]
Precise regulation of the intracellular concentration of chloride [Cl-]i is necessary for proper cell volume regulation, transepithelial transport, and GABA neurotransmission. The Na-K-2Cl (NKCCs) and K-Cl (KCCs) cotransporters, related SLC12A transporters mediating cellular chloride influx and efflux, respectively, are key determinants of [Cl-]i in numerous cell types, including red blood cells, epithelial cells, and neurons. A common "chloride/volume-sensitive kinase", or related system of kinases, has long been hypothesized to mediate the reciprocal but coordinated phosphoregulation of the NKCCs and the KCCs, but the identity of these kinase(s) has remained unknown. Recent evidence suggests that the WNK (with no lysine = K) serine-threonine kinases directly or indirectly via the downstream Ste20-type kinases SPAK/OSR1, are critical components of this signaling pathway. Hypertonic stress (cell shrinkage), and possibly decreased [Cl-]i, triggers the phosphorylation and activation of specific WNKs, promoting NKCC activation and KCC inhibition via net transporter phosphorylation. Silencing WNK kinase activity can promote NKCC inhibition and KCC activation via net transporter dephosphorylation, revealing a dynamic ability of the WNKs to modulate [Cl-]. This pathway is essential for the defense of cell volume during osmotic perturbation, coordination of epithelial transport, and gating of sensory information in the peripheral system. Commiserate with their importance in serving these critical roles in humans, mutations in WNKs underlie two different Mendelian diseases, pseudohypoaldosteronism type II (an inherited form of salt-sensitive hypertension), and hereditary sensory and autonomic neuropathy type 2. WNKs also regulate ion transport in lower multicellular organisms, including Caenorhabditis elegans, suggesting that their functions are evolutionarily-conserved. An increased understanding of how the WNKs regulate the Na-K-2Cl and K-Cl cotransporters may provide novel opportunities for the selective modulation of these transporters, with ramifications for common human diseases like hypertension, sickle cell disease, neuropathic pain, and epilepsy.
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Dev Dyn,
2010]
Asymmetric cell division is an important process to generate cell diversity and maintain tissue homeostasis. Recent evidence suggests that this process may also be crucial to prevent tumor formation. In the past 30 years, the embryo of the nematode Caenorhabditis elegans has proven to be a very powerful model to study the molecular and cellular basis of asymmetric cell division. Understanding this process in Caenorhabditis elegans may thus lead to a better understanding of stem cell function and tumorigenesis in humans.
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Aging Dis,
2016]
Reversible regulation of proteins by reactive oxygen species (ROS) is an important mechanism of neuronal plasticity. In particular, ROS have been shown to act as modulatory molecules of ion channels-which are key to neuronal excitability-in several physiological processes. However ROS are also fundamental contributors to aging vulnerability. When the level of excess ROS increases in the cell during aging, DNA is damaged, proteins are oxidized, lipids are degraded and more ROS are produced, all culminating in significant cell injury. From this arose the idea that oxidation of ion channels by ROS is one of the culprits for neuronal aging. Aging-dependent oxidative modification of voltage-gated potassium (K(+)) channels was initially demonstrated in the nematode Caenorhabditis elegans and more recently in the mammalian brain. Specifically, oxidation of the delayed rectifier KCNB1 (Kv2.1) and of Ca(2+)- and voltage sensitive K(+) channels have been established suggesting that their redox sensitivity contributes to altered excitability, progression of healthy aging and of neurodegenerative disease. Here I discuss the implications that oxidation of K(+) channels by ROS may have for normal aging, as well as for neurodegenerative disease.