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Getty A.L.,University of Rochester | Benedict J.W.,University of Rochester | Pearce D.A.,University of Rochester | Pearce D.A.,Sanford Childrens Health Research Center | Pearce D.A.,University of South Dakota
Experimental Cell Research

Juvenile neuronal ceroid lipofuscinosis (JNCL) is a pediatric lysosomal storage disorder characterized by accumulation of autofluorescent storage material and neurodegeneration, which result from mutations in CLN3. The function of CLN3, a lysosomal membrane protein, is currently unknown. We report that CLN3 interacts with cytoskeleton-associated nonmuscle myosin-IIB. Both CLN3 and myosin-IIB are ubiquitously expressed, yet mutations in either produce dramatic consequences in the CNS such as neurodegeneration in JNCL patients and Cln3-/- mouse models, or developmental deficiencies in Myh10-/- mice, respectively. A scratch assay revealed a migration defect associated with Cln3-/- cells. Inhibition of nonmuscle myosin-II with blebbistatin in WT cells resulted in a phenotype that mimics the Cln3-/- migration defect. Moreover, inhibiting lysosome function by treating cells with chloroquine exacerbated the migration defect in Cln3-/-. Cln3-/- cells traversing a transwell filter under gradient trophic factor conditions displayed altered migration, further linking lysosomal function and cell migration. The myosin-IIB distribution in Cln3-/- cells is elongated, indicating a cytoskeleton defect caused by the loss of CLN3. In summary, cells lacking CLN3 have defects that suggest altered myosin-IIB activity, supporting a functional and physical interaction between CLN3 and myosin-IIB. We propose that the migration defect in Cln3-/- results, in part, from the loss of the CLN3-myosin-IIB interaction. © 2010 Elsevier Inc. Source

Lee L.,Sanford Childrens Health Research Center | Lee L.,University of South Dakota

Motile cilia and flagella are organelles that, historically, have been poorly understood and inadequately investigated. However, cilia play critical roles in fluid clearance in the respiratory system and the brain, and flagella are required for sperm motility. Genetic studies involving human patients and mouse models of primary ciliary dyskinesia over the last decade have uncovered a number of important ciliary proteins and have begun to elucidate the mechanisms underlying ciliary motility. When combined with genetic, biochemical, and cell biological studies in Chlamydomonas reinhardtii, these mammalian genetic analyses begin to reveal the mechanisms by which ciliary motility is regulated. © 2010 Elsevier B.V. Source

Bergeron M.F.,Sanford Sports Science Institute | Bergeron M.F.,University of South Dakota | Bergeron M.F.,Sanford Childrens Health Research Center
Journal of Orthopaedic and Sports Physical Therapy

SYNOPSIS: Running well and safely in the heat is challenging for all runners, from recreational to elite. As environmental heat stress (heat stress modulated or augmented by air temperature, humidity, wind speed, and solar radiation) and the intensity and duration of a training run or race increase, so are metabolic heat production, the parallel need for heat transfer from the body to maintain thermal equilibrium, the consequent increase in blood flow to the skin, and the concomitant sweating response progressively and proportionally amplified. An accumulating total body-water deficit from extensive sweating and escalating level of cardiovascular and thermal strain will, in due course, considerably challenge a runner's physiology, perception of effort, and on-course well-being and performance. However, with the appropriate preparation and modifications to planned running intensity and distance, runners can safely tolerate and effectively train and compete in a wide range of challenging environmental conditions. Clinicians play a key role in this regard as an effective resource for providing the most effective guidelines and making the best overall individual recommendations regarding training and competing in the heat. Copyright © 2014 Journal of Orthopaedic & Sports Physical Therapy. All rights reserved. Source

Carcel-Trullols J.,Sanford Childrens Health Research Center | Kovacs A.D.,Sanford Childrens Health Research Center | Pearce D.A.,Sanford Childrens Health Research Center | Pearce D.A.,University of South Dakota
Biochimica et Biophysica Acta - Molecular Basis of Disease

The fatal, primarily childhood neurodegenerative disorders, neuronal ceroid lipofuscinoses (NCLs), are currently associated with mutations in 13 genes. The protein products of these genes (CLN1 to CLN14) differ in their function and their intracellular localization. NCL-associated proteins have been localized mostly in lysosomes (CLN1, CLN2, CLN3, CLN5, CLN7, CLN10, CLN12 and CLN13) but also in the Endoplasmic Reticulum (CLN6 and CLN8), or in the cytosol associated to vesicular membranes (CLN4 and CLN14). Some of them such as CLN1 (palmitoyl protein thioesterase 1), CLN2 (tripeptidyl-peptidase 1), CLN5, CLN10 (cathepsin D), and CLN13 (cathepsin F), are lysosomal soluble proteins; others like CLN3, CLN7, and CLN12, have been proposed to be lysosomal transmembrane proteins. In this review, we give our views and attempt to summarize the proposed and confirmed functions of each NCL protein and describe and discuss research results published since the last review on NCL proteins. This article is part of a Special Issue entitled: "Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease)". © 2014 Elsevier B.V. Source

Kruer M.C.,Sanford Childrens Health Research Center
International Review of Neurobiology

Neuropathology plays a key role in characterizing the pathogenesis of neurodegenerative diseases including forms of neurodegeneration with brain iron accumulation (NBIA). Despite important differences, several genetically diverse forms of NBIA nevertheless share common features in addition to iron deposition, such as the presence of neuroaxonal spheroids. Multiple forms of NBIA also demonstrate tau or synuclein pathology, suggesting parallels with both Alzheimer and Parkinson diseases. This chapter summarizes what has been learned from the study of human patient tissues. Gross and microscopic findings are delineated, and similarities and differences between forms of NBIA are presented. Neuropathologic findings often help characterize fundamental features of disease and provide a springboard for more focused hypothesis-driven studies. Lessons learned from neuropathology thus contribute much to the characterization of the molecular mechanisms of disease. © 2013 Elsevier Inc. Source

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