Microtubule transport defects in neurological and ciliary disease

Microtubules are primarily responsible for facilitating long-distance transport of both proteins and organelles. Given the critical role of this process in cellular function, it is not surprising that perturbation of microtubule-based transport can lead to diverse phenotypes in humans, including cancer and neurodegenerative disorders such as Alzheimer or Huntington disease. Recent investigations have also indicated that defects in specialized microtubule-based transport systems, such as mutations affecting the transport of protein particles along the length of cilia (intraflagellar transport) can cause retinal dystrophy, polycystic kidney disease or more complex syndromic phenotypes, such as Bardet-Biedl syndrome. In this review, we discuss recent findings implicating defects in microtubule-associated transport and motor proteins in a variety of diseases, particularly the role of defective microtubular transport in neurological and ciliary disease. These defects frequently display phenotypic consequences that manifest as human disease yet do not cause organismal lethality.Received 7 Janury 2005; received after revision 23 February 2005; accepted 21 March 2005     

Potassium-related inherited tubulopathies

Hyper- and hypokalemia may carry severe clinical consequences. Different regulatory mechanisms, including the kidney, exert a tight regulation of plasma potassium levels. The renal pathway of potassium handling begins in the proximal tubule followed by the fine-tuning of its secretion or absorption at the distal tubule, including the thick ascending limb of Henle’s loop, the distal convoluted tubule and the cortical collecting duct. Genetic studies in recent years have clarified the role of specific tubular channels and transporters in the pathogenesis of unique hyper- and hypokalemic tubulopathies, some of them non-hypertensive (pseudohypoaldosteronism, Bartter and Gitelman syndromes) and others hypertensive by definition (including Liddle and Gordon syndromes). This article reviews the genetic and clinical spectrum of hypokalemic and hyperkalemic tubulopathies. Received 13 January 2006; received after revision 19 March 2006; accepted 18 May 2006     

Gaucher disease,a paradigm for single gene defects

Gaucher disease is the most common glycolipid storage disease. Type I, the most common form of the disease, is characterised by enlargement of the liver, and spleen and bone lesions. In the rare type II and type III forms of the disorder, central nervous system involvement is present as well. The disease results from a deficiency of the lysosomal enzyme glucocerebrosidase, which is needed for the enzymatic degradation of complex lipids, globosides and gangliosides. In the absence of sufficient glucocerebrosidase activity, the catabolic product glucocerebroside accumulates.     

The inherited susceptibility to cancer

The study of inherited cancer syndromes has led to the identification of over 25 genes directly involved in tumorigenesis. These genes have functions as diverse as signal transduction, cell cycle control, cell-to-cell adhesion, control of apoptosis, DNA repair and the maintenance of genome stability. Most cancer syndromes have a dominant pattern of inheritance, due to germline loss-of-function mutation of a tumour suppressor gene. All the recessively inherited genes have been implicated in the maintenance of genome stability. This review summarises our current understanding of the functions of the major cancer susceptibility genes.     

LDH isozyme pattern in induced muscle disease (coxsackie group a virus infection)

Résumé Le zymogramme des LDH du muscle de souriceau nouveau-né souffrant de myosite diffuse causée par le virus de Coxsackie Groupe A est semblable à celui du souriceau sain de même âge, suggérant qu'un zymogramme anormal des LDH dans les affections musculaires n'est pathognomonique que chez certaines espèces.     

Celiac disease patient IgA antibodies induce endothelial adhesion and cell polarization defects via extracellular transglutaminase 2

We have recently found that celiac disease patient serum-derived autoantibodies targeted against transglutaminase 2 interfere with several steps of angiogenesis, including endothelial sprouting and migration, though the mechanism involved remained to be fully characterized. This study now investigated the processes underlying the antiangiogenic effects exerted by celiac disease patient antibodies on endothelial cells, with particular regard to the adhesion, migration, and polarization signaling pathway. We observed that celiac IgA reduced endothelial cell numbers by affecting adhesion without increasing apoptosis. Endothelial cells in the presence of celiac IgA showed weak attachment, a high susceptibility to detach from fibronectin, and a disorganized extracellular matrix due to a reduction of protein cross-links. Furthermore, celiac patient IgA led to secretion of active transglutaminase 2 from endothelial cells into the culture supernatants. Additionally, cell surface transglutaminase 2 mediated integrin clustering in the presence of celiac IgA was coupled to augmented expression of β1-integrin. We also observed that celiac patient IgA-treated endothelial cells had migratory defects and a less polarized phenotype when compared to control groups, and this was associated with the RhoA signaling pathway. These biological effects mediated by celiac IgA on endothelial cells were partially influenced but not completely abolished by R281, an irreversible extracellular transglutaminase 2 enzymatic activity inhibitor. Taken together, our results imply that celiac patient IgA antibodies disturb the extracellular protein cross-linking function of transglutaminase 2, thus altering cell-extracellular matrix interactions and thereby affecting endothelial cell adhesion, polarization, and motility.     

Observational defects in eighteenth-century British telescopes

Among the several remarkable properties of mercury is that it dissolves many of the metals (but not iron), forming amalgams. It was the recognition of the ready formation of gold and silver amalgams that led to the extraction of precious metals by the amalgamation method. In this article I trace some of the historical aspects associated with the development of the European amalgamation process, first devised by Ignaz von Born in the 1780s. In particular, I describe an international gathering of experts in mining and metallurgy which was held at Skleno in Slovakia in 1786, and the founding there of a society for mining sciences called ‘Die Societät der Bergbaukunde’.     

Studies on muscle fibre splitting in skeletal muscle

Summary Autoradiographic, stereological and histological studies have been carried out to determine the origin of muscle fibre splitting which supposedly occurs during muscle hypertrophy. The results obtained clearly indicate that the supposedly split fibres are a transient response probably derived from satellite cells and are not derived from pre-existing fibres by true splitting. Similarly, increases in muscle fibre size are not achieved by recruitment of satellite structures as indicated by lack of myonuclear recruitment.Acknowledgment. This work was carried out with the aid of a grant from the Medical Research Council of Great Britain. The authors are grateful for the excellent technical assistance of Miss H. Caulton, M.J. Wild and M. Fenner.     

Retinol and retinyl esters in pigment epithelium of rats with inherited retinal degeneration

Summary A comparative study of the retinol and retinyl ester concentrations was performed in the retinal pigment epithelium of the normal and affected rats. Our findings indicate that in dystrophic rat retinol content increases, whereas the amount of retinyl esters is always lower than normal. An hypothesis can be made on the deficiency of enzymic activities which regulate retinol retinol and retinyl esters levels in the pigment epithelium.     

An inherited glutathione deficiency and a concomitant reduction in potassium concentration in sheep red cells

Resumen Se medió glutation reducido (GSH) en glóbulos rojos de 427 ovejas pertenecientes a 6 razas diferentes. 25% de las ovejas de raza «Finnish Landrace» dieron un contenido de GSH de un tercio del valor obtenido en el resto. Datos familiares indican que esta deficiencia es heredada como un factor autosómico recesivo. En las ovejas que tienen esta deficiencia, la concentracion media de potasio en glóbulos rojos fué significativamente menor que la observada en las ovejas con niveles normales de GSH.     

Retinol and retinyl esters in pigment epithelium of rats with inherited retinal degeneration.

A comparative study of the retinol and retinyl ester concentrations was performed in the retinal pigment epithelium of the normal and affected rats. Our findings indicate that in dystrophic rat retinol content increases, whereas the amount of retinyl esters is always lower than normal. An hypothesis can be made on the deficiency of enzymic activities which regulate retinol retinol and retinyl esters levels in the pigment epithelium.     

Endothelial defects and blood flow disturbance in atherogenesis

Résumé Les observations faites sur le porc de Yorkshire montrent que certaines perturbations du flot sanguin normal se manifestent dans une zone prédisposée au developpement de lésions athéromateuses et sont accompagnées de pertes de substances endothéliales. Cette destruction des cellules endothéliales permettrait au plasma riche en lipoprotéines de pénétrer librement dans la paroi artérielle, ce qui favorise l'athérogénese.

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Supported by NIH grant No. HE 11-11791.     

Malignant hyperthermia: Molecular defects in membrane permeability

Summary Malignant hyperthermia (MH), a genetically inherited disorder of skeletal muscle, is due to molecular defect in membrane permeability. The alteration in membrane permeability is suggested to be due to enhanced phospholipase A₂ activity which is responsible for the increased level in sarcoplasmic Ca²⁺. The excess Ca²⁺ is responsible for muscle hyper-rigidity and enhanced rate of glycolysis, resulting in a rapid rate of lactic acid production and a low pH in MH muscle.     

Contractile properties of fast muscle preparations regenerating in slow muscle beds

Summary Mechanical evidence is presented to show that fast muscle tissue regenerating in the bed of a slow muscle, and innervated by the slow muscle nerve, has contractile properties identical to those of a slow muscle regenerating in its own bed. The results do not support the idea that regenerating fast muscles are partially resistant to the transforming effects of a slow nerve.This investigation was supported in part by NIH grants 1-RO1-NS-14033 and 1-T32-07224.