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Biomedical subjects

Jonathan D Glass

Publications and source records attributed to Jonathan D Glass.

16 recordsLinked to original sources
PubMed2011

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

Adaptor Proteins, Signal Transducing↗
PubMed2006

A multielectrode microcompartment culture platform for studying signal transduction in the nervous system.

This paper describes the design, fabrication, and characterization of a microfabricated compartmented culture system (micro-CCS) useful for electrophysiological signaling studies in cultured neurons. The focus of the paper is the process of interfacing the micro-CCS with cultured neurons and to demonstrate the applicability of the system for biochemical-mediated electrophysiological studies. Moreover, we show that we can record action potentials from cultured neurons through the extracellular compartmented application of elevated levels of K(+) ions. Finally, we show that we can isolate the electrophysiological effects of the sodium channel blocker tetrodotoxin in one of the compartments of a two compartment culture while recording electrophysiological data from both compartments.

Animals↗
PubMed2006

A compartmented neuronal culture system in microdevice format.

This paper describes a microfabricated compartmented culture system (mu-CCS) for studying the effects of drugs on cultured neurons. We describe the fabrication of the microsystem and show the ability to culture DRG neurons in the microsystem. Furthermore, we demonstrate the ability to culture neurons with extensions growing into adjoining compartments while maintaining fluid isolation between compartments. The axonal growth pattern was controlled along the surface of the glass microelectrode substrate using a micropatterned collagen film. The ability to isolate fluids to selected compartments while simultaneously allowing intercompartmental growth of the axons enables various studies in which selected segments of neurons or populations of neurons can be selectively exposed to biochemical treatment. The neurotoxin vincristine was used as the test vehicle to demonstrate the functionality of the mu-CCS. Vincristine was applied to the axonal compartment to show that the interaction of drugs with DRG neurons progresses in a way similar to neurons cultured/exposed using conventional techniques.

Animals↗
PubMed2006

Evidence for direct axonal toxicity in vincristine neuropathy.

There is a long-standing debate concerning the localization of the primary insult that results in distal axonal degeneration, or 'dying back' neuropathy. To address this question, we created an in vitro model of vincristine neuropathy in rat dorsal root ganglia (DRG). DRGs were grown in compartmentalized chambers, allowing for isolated exposure of the cell body or the axon to vincristine. Initial dose-finding studies identified a dose of vincristine that showed differential effects on cell death when delivered to either the cell body or the axonal compartment. At this dose of 0.05 microM, exposure of the cell bodies had no effect on the growth of axons, whereas addition of vincristine to the axonal compartment caused axonal shortening without affecting the growth of unexposed 'sister' axons. Toxicity was seen only with exposure of the growing axonal tips. These data support localized axonal toxicity as a cause of distal axonal degeneration due to vincristine.

Animals↗
PubMed2005

Severe neuropathy with leaky connexin32 hemichannels.

X-linked Charcot-Marie-Tooth disease is one of a set of diseases caused by mutations in gap junction proteins called connexins. We identified a connexin32 missense mutation (F235C) in a girl with unusually severe neuropathy. The localization and trafficking of the mutant protein in cell culture was normal, but electrophysiological studies showed that the mutation caused abnormal hemichannel opening, with excessive permeability of the plasma membrane and decreased cell survival. Abnormal leakiness of connexin hemichannels is likely a mechanism of cellular toxicity in this and perhaps other diseases caused by connexin mutations.

Adolescent↗
PubMed2004

Calpain inhibition protects against Taxol-induced sensory neuropathy.

Taxol is a highly effective anticancer agent that causes peripheral neuropathy as its major toxic side effect. The neuropathy is characterized by degeneration of sensory axons that may be severe enough to be dose limiting. Axonal degeneration involves the activation of the calcium-activated proteases calpains, and here we tested whether systemic inhibition of calpains with the peptide alpha-ketoamide calpain inhibitor AK295 can reduce the clinical and pathological effects of Taxol in a rodent model of Taxol neuropathy. In mice with Taxol neuropathy, AK295 reduced the degree of axonal degeneration in sensory nerve roots, and improved clinical measures of neuropathy, including behavioural and electrophysiological function. These findings were consistent for both 3- and 6-week models of neuropathy. In vitro, Taxol caused activation of both calpains and caspases in PC12 cells. AK295 inhibited the activation of calpains but did not interfere with the antimitotic effects of Taxol on microtubules, nor did it inhibit caspase-mediated cell death. These data implicate calpains in the pathogenesis of Taxol neuropathy, and demonstrate that AK295 can prevent axonal degeneration and clinical neuropathy in mice. In addition, AK295 did not interfere with the primary antineoplastic effects of Taxol on microtubules and cell death, suggesting that systemic calpain inhibition may be a good strategy for preventing neuropathy in patients being treated with Taxol.

Animals↗
PubMed2004

Mitochondrial abnormalities in dermatomyositis: characteristic pattern of neuropathology.

The objective of the work described in this paper was to evaluate mitochondrial abnormalities in perifascicular atrophic fibers in muscle biopsies from patients with dermatomyositis (DM). We localized cytochrome c oxidase (COX) and succinate dehydrogenase (SDH) histochemically in muscle biopsies of 12 patients with DM, and 12 control patients with neurogenic atrophy. These two histochemical techniques were also combined on single tissue sections in order to accentuate any COX-negative fibers. Eleven out of 12 patients (91.6%) with DM showed histochemical evidence of mitochondrial dysfunction in perifascicular distribution. Similar abnormalities in histochemical staining were not seen in comparably sized myofibers that were atrophic due to denervation. It is concluded that abnormal SDH and COX histochemical activities in atrophic perifascicular fibers are characteristic of dermatomyositis. These abnormal staining characteristics could not be accounted for solely by myofiber atrophy, or by generalized abnormalities in histochemical staining.

Adolescent↗
PubMed2004

Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man.

The SOD1 mutant mouse is the most widely used model of human amyotrophic lateral sclerosis (ALS). To determine where and when the pathological changes of motor neuron disease begins, we performed a comprehensive spatiotemporal analysis of disease progression in SOD1(G93A) mice. Quantitative pathological analysis was performed in the same mice at multiple ages at neuromuscular junctions (NMJ), ventral roots, and spinal cord. In addition, a patient with sporadic ALS who died unexpectedly was examined at autopsy. Mice became clinically weak at 80 days and died at 131 +/- 5 days. At 47 days, 40% of end-plates were denervated whereas there was no evidence of ventral root or cell body loss. At 80 days, 60% of ventral root axons were lost but there was no loss of motor neurons. Motor neuron loss was well underway by 100 days. Microglial and astrocytic activation around motor neurons was not identified until after the onset of distal axon degeneration. Autopsy of the ALS patient demonstrated denervation and reinnervation changes in muscle but normal appearing motor neurons. We conclude that in this widely studied animal model of human ALS, and in this single human case, motor neuron pathology begins at the distal axon and proceeds in a "dying back" pattern.

Amyotrophic Lateral Sclerosis↗
PubMed2004

The role of calcitonin gene-related peptide in cutaneous immunosuppression induced by repeated subinflammatory ultraviolet irradiation exposure.

Ultraviolet (UV) light is an effective treatment for skin disorders like psoriasis in which the cutaneous neurosensory system may have a pathogenic role. In this study, we examined the possibility that UV modulation of the cutaneous neurosensory system and calcitonin gene-related peptide (CGRP) may contribute to local immunosuppression mediated by repeated subinflammatory UV irradiation. Our results indicated that exposure of hairless mice to subinflammatory UV three times weekly for 4 weeks significantly increased the number of epidermal nerve fibers (ENFs) immunoreactive for CGRP without altering the total number of ENFs. The skin content of CGRP as measured by enzyme-linked immunosorbent assay was also significantly increased after exposure to this dose of UV. These effects were most apparent 1 day after the last UV exposure and declined 1 week after UV. The role of CGRP in UV-induced immunosuppression of contact hypersensitivity was then examined. Our results indicated that UV suppression of epicutaneous 2,4-dinitro-1-fluorobenzene (DNFB) sensitization could be significantly inhibited by a systemically administered CGRP receptor antagonist. A broad-spectrum sunscreen applied before UV exposure inhibited increased cutaneous CGRP and blocked immunosuppression. These findings support a role for CGRP in the local immunosuppression caused by chronic, repeated subinflammatory UV exposure.

Animals↗
PubMed2003

Stable inheritance of an 85-kb triplication in C57BL/WldS mice.

The slow Wallerian degeneration mouse, C57BL/Wld(S), carries a dominant mutation that delays Wallerian degeneration in the distal stump of an injured axon. A highly unusual mutation, an 85-kb tandem triplication in the Wld(S) mouse was identified. Since two duplication cases have been identified before, pulsed field gel electrophoresis (PFGE) can be used to look for the instability of triplication at the chromosomal level. One hundred and eighty chromosomes of Wld(S) from three divergent breeding colonies have been examined and all found to carry the triplication. Thus, the triplication mutation is stable during both mitosis and meiosis, and the previously observed duplication is likely to have been surviving alleles of the original mutation rather than a partial reversion. The triplication has now been shown to be the causative mutation, acting through an Ube4b/Nmnat chimeric gene, indicating the possibility of Wld(S) preventing axon degeneration in diverse pathologies and altering the symptoms. The fact that triplication is stable rules out instability as a source of phenotypic variation. Thus, this result is essential for accurate interpretation of studies the effect of Wld(S) on neurodegenerative phenotypes.

Aging↗
PubMed2002

Very early activation of m-calpain in peripheral nerve during Wallerian degeneration.

Peripheral nerve injury results in a series of events culminating in degradation of the axonal cytoskeleton (Wallerian degeneration). In the time period between axotomy and cytoskeletal degradation (24-48 h in rodents), there is calcium entry and activation of calpains within the axon. The precise timing of these events during this period is unknown. In the present study, antibodies were generated to three distinct peptide epitopes of m-calpain, and a fusion protein antibody was generated to the intrinsic calpain inhibitor calpastatin. These antibodies were used to measure changes in these proteins in mouse sciatic nerves during Wallerian degeneration. In sciatic nerve homogenates and cultured dorsal root ganglion (DRG) neurites, m-calpain protein was significantly reduced in transected nerves very early after nerve injury, long before axonal degeneration occurred. Levels of m-calpain protein remained low as compared to control nerves for the remainder of the 72-h time course. No changes in calpastatin protein were evident. Systemic treatment of animals with the protease inhibitor leupeptin partially prevented the rapid loss of calpain protein. Removal of calcium in DRG cultures had the same effect. These data indicate that m-calpain protein is lost very early after axonal injury, and likely reflect activation and degradation of this protein long before the cytoskeleton is degraded. Calpain activation may be an early event in a proteolytic cascade that is initiated by axonal injury and culminates with axonal degeneration.

Animals↗
PubMed2002

WldS mice are resistant to paclitaxel (taxol) neuropathy.

The WldS mouse is a unique mutant strain that demonstrates the remarkable phenotype of prolonged survival of transected axons ("slow Wallerian degeneration"). In these studies, we tested whether this neuroprotective phenotype extends to axonal degeneration seen in a progressive peripheral neuropathy. WldS and wild-type mice were intoxicated with the cancer chemotherapeutic agent paclitaxel (Taxol). The severity of the resultant sensory neuropathy was compared with behavioral, physiological, and pathological measures. WldS mice were resistant to paclitaxel neuropathy by all measures, and the resistance was because of protection against axonal degeneration. These studies demonstrate for the first time that the WldS mouse is more than a slow Wallerian degeneration phenotype, emphasizing the mechanistic link between Wallerian degeneration and peripheral neuropathy. Understanding how this mutant gene confers protection against axonal degeneration will provide important clues toward prevention of axonal degeneration in several human neurological disorders.

Animals↗
PubMed2002

A practical approach to the diagnosis and management of MELAS: case report and review.

BACKGROUND: Mitochondrial encephalomyopathy, lactic acidosis with stroke-like episodes (MELAS) is a mitochondrial disorder and an important diagnostic consideration in the young patient with nonhemorrhagic stroke. Its presentation is varied and diagnosis is based on early recognition of the clinical features and correct interpretation of laboratory and radiologic studies. SUMMARY: In this article, we report a patient with MELAS and review the clinical, laboratory, and neuroradiologic features of the condition. In the young patient with multiple stroke-like episodes in different vascular territories and neuroradiologic features of transient abnormalities in varying regions, laboratory testing for MELAS must be performed. The presence of ragged red fibers in skeletal muscle and biochemical demonstration of defects in mitochondrial respiratory enzymes strongly support the diagnosis. Molecular genetic testing for abnormalities in mitochondrial DNA will confirm the diagnosis. The importance of a thorough assessment of family history is also emphasized. The basic principles of mitochondrial genetics and the common point mutations and rearrangements of mitochondrial DNA associated with MELAS are reviewed. Although treatment options are limited, several therapeutic agents have been studied. CONCLUSIONS: The diagnosis of MELAS should be considered in the young patient with stroke, especially when accompanied by other clinical features such as seizures, encephalopathy, and muscle weakness. Laboratory evaluation can provide an accurate diagnosis, especially when the appropriate mitochondrial DNA studies are performed. Genetic counseling should be provided to patients with MELAS associated with mitochondrial DNA point mutations. Better understanding of the molecular basis of the condition may result in the development of effective treatment strategies.

Journal Article↗
PubMedDate not supplied

The WldS gene modestly prolongs survival in the SOD1G93A fALS mouse.

The "slow Wallerian degeneration" (Wld(S)) gene is neuroprotective in numerous models of axonal degeneration. Axonal degeneration is an early feature of disease progression in the SOD1G93A mouse, a widely used model of familial amyotrophic lateral sclerosis (fALS). We crossed the Wld(S) mouse with the SOD1G93A mouse to investigate whether the Wld(S) gene could prolong survival and modify neuropathology in these mice. SOD/Wld(S) mice showed levels of motor axon loss similar to that seen in SOD1G93A mice. The presence of the Wld(S) gene, however, modestly prolonged survival and delayed denervation at the neuromuscular junction. Prolonged survival was more prominent in female mice and did not depend on whether animals were heterozygous or homozygous for the Wld(S) gene. We also report that SOD1G93A mice show significant degeneration of sensory axons during the course of disease, supporting previous data from humans demonstrating that ALS is not purely a motor disorder.

Amyotrophic Lateral Sclerosis↗