Papers by Henry Waldvogel
Brain, 2010
Huntington's dise... more Huntington's disease is an autosomal dominant inherited neurodegenerative disease with motor symptoms that are variably co-expressed with mood and cognitive symptoms, and in which variable neuronal degeneration is also observed in the basal ganglia and the cerebral cortex. We have recently shown that the variable symptomatology in Huntington's disease correlates with the variable compartmental pattern of GABAA receptor and cell loss in the striatum. To determine whether the phenotypic variability in Huntington's disease is also related to variable neuronal degeneration in the cerebral cortex, we undertook a double-blind study using unbiased stereological cell counting methods to determine the pattern of cell loss in the primary motor and anterior cingulate cortices in the brains of 12 cases of Huntington's disease and 15 controls, and collected detailed data on the clinical symptomatology of the patients with Huntington's disease from family members and clinical records. The results showed a significant association between: (i) pronounced motor dysfunction and cell loss in the primary motor cortex; and (ii) major mood symptomatology and cell loss in the anterior cingulate cortex. This association held for both total neuronal loss (neuronal N staining) and pyramidal cell loss (SMI32 staining), and also correlated with marked dystrophic changes in the remaining cortical neurons. There was also an association between cortical cell loss and striatal neuropathological grade, but no significant association with CAG repeat length in the Huntington's disease gene. These findings suggest that the heterogeneity in clinical symptomatology that characterizes Huntington's disease is associated with variation in the extent of cell loss in the corresponding functional regions of the cerebral cortex whereby motor dysfunction correlates with primary motor cortex cell loss and mood symptomatology is associated with cell loss in the cingulate cortex.
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Annals of Neurology, 2015
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Journal of Neurochemistry, 2015
Huntington&#3... more Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an expansion of the CAG repeat in the huntingtin gene. One of the brain changes that occurs in HD is the expression of the Receptor for Advanced Glycation End products (RAGE), a receptor protein capable of activating multiple signalling pathways by interacting with a range of ligands leading to either beneficial or harmful effects to the cell. Here we demonstrate in human HD brains a high degree of colocalisation of RAGE with its putative ligands S100B and carboxymethyllysine (CML) in the caudate nucleus (CN) and the subependymal layer (SEL). The level of co-staining for both RAGE-S100B and RAGE-CML was the highest in the astrocytes but was low in neurons and microglia. The immunostaining for RAGE, S100B and CML extended in a medio-lateral (SEL-CN) direction with increasing grade, such that any change in the expression and colocalisation pattern between grades was less prominent in the lateral CN. Additionally, signalling molecules that are downstream of RAGE activation showed changes in their activation status in HD brains. A larger number of RAGE-positive astrocytic cells had NF-kB translocated to the nucleus and the level of phospho-ERK1/2 was also increased in HD brains. Interestingly, the level of mDia-1, that interacts directly with the cytoplasmic domain of RAGE, decreased in HD. Overall, the results suggest a correlation between the functions of RAGE and the HD pathology, but the influence of RAGE on astrocytes and the impact of this on HD progression requires further study. This article is protected by copyright. All rights reserved.
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Annals of Clinical and Translational Neurology, 2015
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Journal of neural transmission. Supplementum, 2009
The substantia nigra pars compacta (SNc) is comprised mainly of dopaminergic pigmented neurons ar... more The substantia nigra pars compacta (SNc) is comprised mainly of dopaminergic pigmented neurons arranged in groups, with a small population of nonpigmented neurons scattered among these groups. These different types of neurons possess GABAA, GABAB, and glycine receptors. The SNc-pigmented dopaminergic neurons have postsynaptic GABAA receptors (GABAAR) with a subunit configuration containing alpha3 and gamma2 subunits, with a small population of pigmented neurons containing alpha1 beta2,3 gamma2 subunits. GABAB receptors comprised of R1 and R2 subunits and glycine receptors are also localized on pigmented neurons. In contrast, nonpigmented (mainly parvalbumin positive neurons) located in the SNc are morphologically and neurochemically similar to substantia nigra pars reticulata (SNr) neurons by showing immunoreactivity for parvalbumin and GABAARs containing immunoreactivity for alpha1, alpha3, beta2,3, and gamma2 subunits as well as GABAB R1 and R2 subunits and glycine receptors. Thus...
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Neuroscience, 2000
Severe perinatal asphyxia can lead to injury and dysfunction of the basal ganglia. Post insult ad... more Severe perinatal asphyxia can lead to injury and dysfunction of the basal ganglia. Post insult administration of insulin-like growth factor-1 is neuroprotective, particularly in the striatum. Insulin-like growth factor-1 is also known to be a neuromodulator of several types of striatal neurons. The striatum comprises various phenotypic neurons with a complex neurochemical anatomy and physiology. In the present study, we examined the specificity of neuronal rescue with insulin-like growth factor-1 on different striatal neurons. Bilateral brain injury was induced in near term fetal sheep by 30 min of reversible carotid artery occlusion. A single dose of 3 microg of insulin-like growth factor-1 was infused over 1 h into the lateral ventricle 90 min following ischemia. The histological and immunohistochemical outcome were examined after 4 days recovery using paraffin tissue preparations. Insulin-like growth factor-1 treatment (n = 11) significantly reduced the percentage of neuronal los...
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Journal of Huntington's disease, 2012
We review recent investigations regarding the relationship between selective neurodegeneration in... more We review recent investigations regarding the relationship between selective neurodegeneration in the human brain and the variability in symptom profiles in Huntington's disease. Huntington's disease is a genetic neurodegenerative disorder caused by an expanded CAG repeat in exon 1 of the Huntingtin gene on chromosome 4, encoding a protein called huntingtin. The huntingtin protein is expressed ubiquitously in somatic tissue, however, the major pathology affects the brain with profound degeneration in the striatum and the cerebral cortex. Despite the disease being caused by a single gene, there is a major variability in the neuropathology, as well as major heterogeneity in the symptom profiles observed in Huntington's disease patients. The symptoms may vary throughout the disease course and present as varying degrees of movement disorder, cognitive decline, and mood and behavioral changes. To determine whether there is an anatomical basis underlying symptom variation, rec...
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Journal of Huntington's disease, 2014
Huntington's disease is an autosomal dominant neurodegenerative disease characterized by neur... more Huntington's disease is an autosomal dominant neurodegenerative disease characterized by neuronal degeneration in the basal ganglia and cerebral cortex, and a variable symptom profile. Although progressive striatal degeneration is known to occur and is related to symptom profile, little is known about the cellular basis of symptom heterogeneity across the entire cerebral cortex. To investigate this, we have undertaken a double blind study using unbiased stereological cell counting techniques to determine the pattern of cell loss in six representative cortical regions from the frontal, parietal, temporal, and occipital lobes in the brains of 14 Huntington's disease cases and 15 controls. The results clearly demonstrate a widespread loss of total neurons and pyramidal cells across all cortical regions studied, except for the primary visual cortex. Importantly, the results show that cell loss is remarkably variable both within and between Huntington's disease cases. The res...
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Science Translational Medicine, 2014
Age-related neurodegenerative disorders including Alzheimer&a... more Age-related neurodegenerative disorders including Alzheimer's disease and Huntington's disease (HD) consistently show elevated DNA damage, but the relevant molecular pathways in disease pathogenesis remain unclear. One attractive gene is that encoding the ataxia-telangiectasia mutated (ATM) protein, a kinase involved in the DNA damage response, apoptosis, and cellular homeostasis. Loss-of-function mutations in both alleles of ATM cause ataxia-telangiectasia in children, but heterozygous mutation carriers are disease-free. Persistently elevated ATM signaling has been demonstrated in Alzheimer's disease and in mouse models of other neurodegenerative diseases. We show that ATM signaling was consistently elevated in cells derived from HD mice and in brain tissue from HD mice and patients. ATM knockdown protected from toxicities induced by mutant Huntingtin (mHTT) fragments in mammalian cells and in transgenic Drosophila models. By crossing the murine Atm heterozygous null allele onto BACHD mice expressing full-length human mHTT, we show that genetic reduction of Atm gene dosage by one copy ameliorated multiple behavioral deficits and partially improved neuropathology. Small-molecule ATM inhibitors reduced mHTT-induced death of rat striatal neurons and induced pluripotent stem cells derived from HD patients. Our study provides converging genetic and pharmacological evidence that reduction of ATM signaling could ameliorate mHTT toxicity in cellular and animal models of HD, suggesting that ATM may be a useful therapeutic target for HD.
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Journal of Huntington's disease, 2013
Huntington's disease is a neurodegenerative disorder, typically with clinical manifestations ... more Huntington's disease is a neurodegenerative disorder, typically with clinical manifestations in adult years, caused by an expanded polyglutamine-coding repeat in HTT. There are no treatments that delay or prevent the onset or progression of this devastating disease. In order to study its pre-symptomatic molecular progression and provide a large mammalian model for determining natural history of the disease and for therapeutic testing, we generated and previously reported on lines of transgenic sheep carrying a full length human HTT cDNA transgene, with expression driven by a minimal HTT promoter. We report here further characterization of our preferred line, OVT73. This line reliably expresses the expanded human huntingtin protein at modest, but readily detectable levels throughout the brain, including the striatum and cortex. Transmission of the 73 unit glutamine coding repeat was relatively stable over three generations. At the first time-point of a longitudinal study, animals...
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Advances in Behavioral Biology, 2002
Parkinson’s disease (PD) is one of the most common human neurodegenerative diseases and is charac... more Parkinson’s disease (PD) is one of the most common human neurodegenerative diseases and is characterized by the loss of nigrostriatal dopaminergic neurons leading to a deficiency in dopaminergic neurotransmission. So far, there is no effective treatment for preventing the degeneration of nigrostriatal neurons in Parkinson’s disease. IGF-1 is neuroprotective after various types of brain injuriesin vivo(Guan et al., 1993; Johnston
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Advances in Behavioral Biology, 2009
We have investigated the cellular localisation of GABAA (GABAAR) and glycine (GLYR) receptors in ... more We have investigated the cellular localisation of GABAA (GABAAR) and glycine (GLYR) receptors in the human basal ganglia using immunohistochemical techniques and light and confocal laser scanning microscopy. GABAAR were most highly expressed on GABAergic striatal interneurons (α1, β2,3, γ2 subunits), cholinergic interneurons (α3), and striatal projection neurons (α2, α3, β2,3, γ2 subunits). GLYR were present mainly on ChAT and
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PLoS ONE, 2008
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Neuroscience, 1995
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Neuroscience, 1995
GABA and GABAA receptors have been studied in the substantia nigra of the rat following quinolini... more GABA and GABAA receptors have been studied in the substantia nigra of the rat following quinolinic acid lesions in the striatum. The regional distribution of GABA and GABAA receptors was investigated using immunohistochemical techniques with monoclonal antibodies to GABA and to the beta 2.3 subtypes of the GABAA receptor complex. The distribution, density and cellular localization of GABAA receptors were studied using quantitative receptor autoradiography and 6-hydroxydopamine-induced degeneration of dopaminergic pars compacta neurons. The subunit configuration of GABAA receptors was investigated using in situ hybridization histochemistry and subunit subtype-specific oligonucleotide probes. The results showed that in the normal substantia nigra GABA and GABAA receptors were mainly localized within the pars reticulata. GABAA receptors were mainly of the BZI variety, had a subunit subtype configuration that included alpha 1 and beta 2.3 subtypes, and showed a rostrocaudal gradient in the density of receptors; the density of receptors in the caudal third was 56% higher than that in the rostral third of the pars reticulata. Following quinolinic acid-induced degeneration of the striatonigral pathway, there was a marked loss of GABA immunoreactivity and a 59% increase in the density of GABAA receptors in the substantia nigra pars reticulata. There was a corresponding regional topography in the pattern of loss of GABA immunoreactivity and in the pattern of increase in GABAA receptors in the pars reticulata; the topography varied with the size and placement of the lesion in the striatum and correlated with the known topographical organization of the striatonigral projection. The quantitative autoradiographic results showed that following quinolinic acid lesions in the striatum: (i) the greatest increase in the density of GABAA receptors occurred in the middle third (91% increase) of the pars reticulata; (ii) the receptors were mainly of the GABAA/BZI variety; and (iii) 6-hydroxydopamine-induced degeneration of the dopaminergic pars compacta neurons did not significantly affect the density of receptors, indicating that the increased receptor binding was mainly localized on non-dopaminergic pars reticulata neurons. The immunohistochemical and in situ hybridization studies showed that, as in the normal substantia nigra, GABAA receptors in the substantia nigra pars reticulata on the lesioned side contained the alpha 1 and beta 2.3 GABAA receptor subtypes; the alpha 1 and beta 2.3 subtypes (but not the alpha 2) were increased after quinolinic acid lesions.(ABSTRACT TRUNCATED AT 400 WORDS)
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Neuroscience, 2003
Gephyrin is an ubiquitously expressed protein that, in the central nervous system, generates a pr... more Gephyrin is an ubiquitously expressed protein that, in the central nervous system, generates a protein scaffold to anchor inhibitory neurotransmitter receptors in the postsynaptic membrane. It was first identified as a protein component of the glycine receptor complex. Recent studies have demonstrated that gephyrin is colocalized with several subtypes of GABA(A) receptors and is part of postsynaptic GABA(A) receptor clusters. Here, we describe a study of the regional and cellular distribution of gephyrin in the human brain, determined by immunohistochemical localisation at the light and confocal laser scanning microscopic levels. At the regional level, gephyrin immunoreactivity was observed in most of the major brain regions examined. The most intense staining was in the cerebral cortex, hippocampus and caudate-putamen, in various brainstem nuclei with more moderate levels in the thalamus and cerebellum. At the cellular level gephyrin immunoreactivity was present on the plasma membranes of the soma and dendrites of pyramidal neurons throughout the various cortical regions examined. In the hippocampus, intense staining was observed on the granule cells of the dentate gyrus, and neurons of the CA1 and CA3 regions showed intense punctate gephyrin staining on their apical dendrites and cell bodies. Gephyrin immunoreactivity was also observed on neurons in the thalamus, globus pallidus and substantia nigra. In the putamen intense labelling of the striosomes was observed; most of the medium-sized neurons in the caudate-putamen were weakly labelled and many large neurons of the striatum were conspicuously stained. Many of the brainstem nuclei, notably the dorsal motor nucleus of the vagus, hypoglossal nucleus, trigeminal nucleus and inferior olive were all labelled with gephyrin. The spinal cord also showed high levels of gephyrin immunoreactivity. Our results demonstrate that the anchoring protein gephyrin is ubiquitously present in the human brain. We therefore suggest that gephyrin may have a central organizer role in assembling and stabilizing inhibitory postsynaptic membranes in human brain and is similar in function to those observed in the rodent brain. These findings contribute towards elucidating the role of gephyrin in the human brain.
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NeuroReport, 1999
The cellular distribution of the type VI human voltage-gated sodium channel (Type VI) was examine... more The cellular distribution of the type VI human voltage-gated sodium channel (Type VI) was examined in selected human brain regions. Antibodies designed to be specific to rat and human Type VI were raised against a synthetic peptide from the predicted NH2-terminal of the protein, and used for an immunohistochemical investigation. Immunoblot experiments showed that purified antibodies specifically detected the presence of Type VI in transfected cells and human brain membrane preparations. Immunohistochemistry on perfusion fixed human tissue revealed a predominantly somato-dendritic distribution of Type VI in major output neurons of the cerebellum, cerebral cortex and hippocampus. The observed localisation of this channel may reflect an important role in the integration of synaptic input in the human CNS.
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Nature Protocols, 2007
One of the challenges for modern neuroscience is to understand the basis of coordinated neuronal ... more One of the challenges for modern neuroscience is to understand the basis of coordinated neuronal function and networking in the human brain. Some of these questions can be addressed using low- and high-resolution imaging techniques on post-mortem human brain tissue. We have established a versatile protocol for fixation of post-mortem adult human brain tissue, storage of the tissue in a human brain bank, and immunohistochemical analysis in order to understand human brain functions in normal controls and in neuropathological conditions. The brains are fixed by perfusion through the internal carotid and basilar arteries to enhance the penetration of fixative throughout the brain, then blocked, postfixed, cryoprotected, snap-frozen and stored at -80 degrees C. Sections are processed for immunohistochemical single- or double-label staining and conventional-, electron- or confocal laser scanning-microscopy analysis. The results gained using this tissue and protocol are vital for determining the localization of neurochemicals throughout the human brain and to document the changes that occur in neurological diseases.
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Nature Methods, 2011
Human diseases are often accompanied by histological changes that confound interpretation of mole... more Human diseases are often accompanied by histological changes that confound interpretation of molecular analyses and identification of disease-related effects. We developed population-specific expression analysis (PSEA), a computational method of analyzing gene expression in samples of varying composition that can improve analyses of quantitative molecular data in many biological contexts. PSEA of brains from individuals with Huntington's disease revealed myelin-related abnormalities that were undetected using standard differential expression analysis.
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Journal of Neurochemistry, 2007
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Papers by Henry Waldvogel