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Showing papers on "Neurodegeneration published in 1997"


Journal ArticleDOI
28 Aug 1997-Nature
TL;DR: Strong staining of Lewy bodies from idiopathic Parkinson's disease with antibodies for α-synuclein, a presynaptic protein of unknown function which is mutated in some familial cases of the disease, indicates that the LewY bodies from these two diseases may have identical compositions.
Abstract: Lewy bodies, a defining pathological characteristic of Parkinson's disease and dementia with Lewy bodies (DLB)1,2,3,4, constitute the second most common nerve cell pathology, after the neurofibrillary lesions of Alzheimer's disease. Their formation may cause neurodegeneration, but their biochemical composition is unknown. Neurofilaments and ubiquitin are present5,6,7,8, but it is unclear whether they are major components of the filamentous material of the Lewy body9,10. Here we describe strong staining of Lewy bodies from idiopathic Parkinson's disease with antibodies for α-synuclein, a presynaptic protein of unknown function which is mutated in some familial cases of the disease11. α-Synuclein may be the main component of the Lewy body in Parkinson's disease. We also show staining for α-synuclein of Lewy bodies from DLB, indicating that the Lewy bodies from these two diseases may have identical compositions.

6,923 citations


Journal ArticleDOI
26 Sep 1997-Science
TL;DR: An NH2-terminal fragment of mutant huntingtin was localized to neuronal intranuclear inclusions and dystrophic neurites in the HD cortex and striatum, and polyglutamine length influenced the extent of huntingtin accumulation in these structures.
Abstract: The cause of neurodegeneration in Huntington's disease (HD) is unknown. Patients with HD have an expanded NH2-terminal polyglutamine region in huntingtin. An NH2-terminal fragment of mutant huntingtin was localized to neuronal intranuclear inclusions (NIIs) and dystrophic neurites (DNs) in the HD cortex and striatum, which are affected in HD, and polyglutamine length influenced the extent of huntingtin accumulation in these structures. Ubiquitin was also found in NIIs and DNs, which suggests that abnormal huntingtin is targeted for proteolysis but is resistant to removal. The aggregation of mutant huntingtin may be part of the pathogenic mechanism in HD.

2,731 citations


Journal ArticleDOI
08 Aug 1997-Cell
TL;DR: In this study, it is shown that the proteolytic cleavage of a GST-huntingtin fusion protein leads to the formation of insoluble high molecular weight protein aggregates only when the polyglutamine expansion is in the pathogenic range.

1,295 citations


Journal ArticleDOI
01 Aug 1997-Neuron
TL;DR: It is suggested that intranuclear aggregation of the expanded protein is a unifying feature of CAG/polyglutamine diseases and may be initiated or catalyzed by a glutamine-containing fragment of the disease protein.

823 citations


Journal ArticleDOI
TL;DR: Control the local inflammatory microenvironment of SP may hold promise for slowing lesion pathogenesis, but it still remains a fundamental challenge to determine the mechanism of neurodegeneration that results in widespread neurofibrillary degeneration and eventual synaptic and neuronal loss.
Abstract: Senile plaques (SP) are complicated lesions composed of diverse amyloid peptides and associated molecules, degenerating neuronal processes,a nd reactive glia. Evidence suggests that diffuse, neurocentric amyloid deposits evolve over time with formation of discrete niduses that eventually become neuritic SP. The evidence for differential amyloid precursor protein metabolism that may favor deposition of A beta 17-42 in this early, possibly aging-related lesion is discussed. This latter molecule, also known as P3, may represent a benign form of amyloid, since it lacks domains associated with activation and recruitment of glia to SP. Subsequent to deposition of A beta 1-42 and then growth of the amyloid with precipitation of soluble A beta 1-40, in an Alzheimer disease-specific process, SP increasingly become associated with activated microglia and reactive astrocytes. In response to interaction with amyloid peptides and possibly glycated proteins, microglia and astrocytes produce a number of molecules that may be locally toxic to neuronal processes in the vicinity of SP, including cytokines, reactive oxygen and nitrogen intermediates, and proteases. They also produce factors that lead to their reciprocal activation and growth, which potentiate a local inflammatory cascade. Paired helical filament- (PHF) type neurites appear to be associated with SP only in so far as neurofibrillary degeneration has progressed to affect neurons in those regions where the plaque forms. Thus, PHF-type neurites are readily apparent in SP in the amygdala at an early stage, while they are late in primary cortices and never detected in cerebellar plaques; where only dystrophic neurites are detected. If the various stages of SP pathogenesis can be further clarified, it may be possible to develop rational approaches to therapy directed at site-, cell type-, and stage-specific interventions. Although controlling the local inflammatory microenvironment of SP may hold promise for slowing lesion pathogenesis, it still remains a fundamental challenge to determine the mechanism of neurodegeneration that results in widespread neurofibrillary degeneration and eventual synaptic and neuronal loss, which is considered to be the proximate cause of the clinical dementia syndrome.

706 citations


Journal ArticleDOI
TL;DR: Evidence for the contribution of cytokines to acute neurodegeneration is reviewed, focusing primarily on interleukin 1 (IL-1), tumour necrosis factor-alpha (TNFalpha) and transforming growth factor-beta (TGFbeta).
Abstract: Cytokines have been implicated as mediators and inhibitors of diverse forms of neurodegeneration. They are induced in response to brain injury and have diverse actions that can cause, exacerbate, mediate and/or inhibit cellular injury and repair. Here we review evidence for the contribution of cytokines to acute neurodegeneration, focusing primarily on interleukin 1 (IL-1), tumour necrosis factor-alpha (TNFalpha) and transforming growth factor-beta (TGFbeta). TGFbeta seems to exert primarily neuroprotective actions, whereas TNFalpha might contribute to neuronal injury and exert protective effects. IL-1 mediates ischaemic, excitotoxic and traumatic brain injury, probably through multiple actions on glia, neurons and the vasculature. Understanding cytokine action in acute neurodegeneration could lead to novel and effective therapeutic strategies, some of which are already in clinical trials.

626 citations


Journal ArticleDOI
TL;DR: The role of apoptotic cell death in the development of the nervous system and as a response to neuronal injury is discussed and the evidence for a role for these cell death regulators in neuronal death decisions is discussed.
Abstract: A growing family of genes that share homology with the bcl-2 proto-oncogene is involved in the regulation of cell death Many of these proteins show widespread expression and are expressed in the nervous system in developing and adult organisms A physiologic role for Bcl-2 and Bcl-x in neuron survival has been shown In addition, these proteins have been shown to protect neurons from a wide array of toxic insults In this review, we discuss the Bcl-2 family of proteins with regard to their structure and interactions We then discuss the role of apoptotic cell death in the development of the nervous system and as a response to neuronal injury Lastly, we discuss the evidence for a role for these cell death regulators in neuronal death decisions

600 citations


Journal ArticleDOI
TL;DR: It is reported that Aβ impairs glucose transport in cultured rat hippocampal and cortical neurons by a mechanism involving membrane lipid peroxidation and suggested that this action of Aβ may contribute to decreased glucose uptake and neuronal degeneration in AD.
Abstract: A deficit in glucose uptake and a deposition of amyloid beta-peptide (A beta) each occur in vulnerable brain regions in Alzheimer's disease (AD). It is not known whether mechanistic links exist between A beta deposition and impaired glucose transport. We now report that A beta impairs glucose transport in cultured rat hippocampal and cortical neurons by a mechanism involving membrane lipid peroxidation. A beta impaired 3H-deoxy-glucose transport in a concentration-dependent manner and with a time course preceding neurodegeneration. The decrease in glucose transport was followed by a decrease in cellular ATP levels. Impairment of glucose transport, ATP depletion, and cell death were each prevented in cultures pretreated with antioxidants. Exposure to FeSO4, an established inducer of lipid peroxidation, also impaired glucose transport. Immunoprecipitation and Western blot analyses showed that exposure of cultures to A beta induced conjugation of 4-hydroxynonenal (HNE), an aldehydic product of lipid peroxidation, to the neuronal glucose transport protein GLUT3. HNE induced a concentration-dependent impairment of glucose transport and subsequent ATP depletion. Impaired glucose transport was not caused by a decreased energy demand in the neurons, because ouabain, which inhibits Na+/K(+)-ATPase activity and thereby reduces neuronal ATP hydrolysis rate, had little or no effect on glucose transport. Collectively, the data demonstrate that lipid peroxidation mediates A beta-induced impairment of glucose transport in neurons and suggest that this action of A beta may contribute to decreased glucose uptake and neuronal degeneration in AD.

555 citations


Journal ArticleDOI
21 Aug 1997-Nature
TL;DR: The activation of apoptotic neuronal death in Lurcher mice may provide a physiologically relevant model for excitotoxic cell death, demonstrating that Lc is inherited as a neurodegenerative disorder resulting from a gain-of-function mutation in a glutamate receptor gene.
Abstract: Lurcher (Lc) is a spontaneous, semidominant mouse neurological mutation. Heterozygous Lurcher mice (Lc/+) display ataxia as a result of a selective, cell-autonomous and apoptotic death of cerebellar Purkinje cells during postnatal development. Homozygous Lurcher mice (Lc/Lc) die shortly after birth because of a massive loss of mid- and hindbrain neurons during late embryogenesis. We have used positional cloning to identify the mutations responsible for neurodegeneration in two independent Lc alleles as G-to-A transitions that change a highly conserved alanine to a threonine residue in transmembrane domain III of the mouse delta2 glutamate receptor gene (GluR delta2). Lc/+ Purkinje cells have a very high membrane conductance and a depolarized resting potential, indicating the presence of a large, constitutive inward current. Expression of the mutant GluR delta2(Lc) protein in Xenopus oocytes confirmed these results, demonstrating that Lc is inherited as a neurodegenerative disorder resulting from a gain-of-function mutation in a glutamate receptor gene. Thus the activation of apoptotic neuronal death in Lurcher mice may provide a physiologically relevant model for excitotoxic cell death.

545 citations


Journal ArticleDOI
TL;DR: Results support and extend previous findings that BDNF mRNA is reduced in the human Alzheimer's disease hippocampus and temporal cortex, and suggest that a loss of BDNF may contribute to the progressive atrophy of neurons in Alzheimer’s disease.

535 citations


Journal ArticleDOI
TL;DR: It is reported that certain strains of mice, including strains that are used for gene targeting studies, do not exhibit excitotoxic cell death after kainic acid seizures, and it is demonstrated that C57BL/6 and BALB/c strains carry gene(s) that convey protection from glutamate-inducedexcitotoxicity.
Abstract: Recent studies have sought to identify the genes involved in excitotoxic neurodegeneration. Here we report that certain strains of mice, including strains that are used for gene targeting studies, do not exhibit excitotoxic cell death after kainic acid seizures. Kainic acid produced excitotoxic cell death in the CA3 and CA1 subfields of the hippocampus in 129/SvEMS and FVB/N mice, in the same pattern as described in rats. C57BL/6 and BALB/c mice exhibited excitotoxic cell death only at very high doses of kainate, and then only in a very restricted area, although they exhibited comparable seizures. Hybrids of 129/SvEMS × C57BL/6 mice created using embryonic stem cells from 129/SvEMS mice also did not exhibit excitotoxic cell death. These results demonstrate that C57BL/6 and BALB/c strains carry gene(s) that convey protection from glutamate-induced excitotoxicity. This differential susceptibility to excitotoxicity represents a potential complication for gene targeting studies.

Journal ArticleDOI
09 Oct 1997-Nature
TL;DR: It is reported that TGF-β1 induces amyloid-β deposition in cerebral blood vessels and meninges of aged transgenic mice overexpressing this cytokine from astrocytes, and so may be a risk factor for developing Alzheimer's disease.
Abstract: Deposition of amyoid-beta peptide in the central nervous system is a hallmark of Alzheimer's disease and a possible cause of neurodegeneration. The factors that initiate or promote deposition of amyloid-beta peptide are not known. The transforming growth factor TGF-beta1 plays a central role in the response of the brain to injury, and increased TGF-beta1 has been found in the central nervous system of patients with Alzheimer's disease. Here we report that TGF-beta1 induces amyloid-beta deposition in cerebral blood vessels and meninges of aged transgenic mice overexpressing this cytokine from astrocytes. Co-expression of TGF-beta1 in transgenic mice overexpressing amyloid-precursor protein, which develop Alzheimer's like pathology, accelerated the deposition of amyloid-beta peptide. More TGF-beta1 messenger RNA was present in post-mortem brain tissue of Alzheimer's patients than in controls, the levels correlating strongly with amyloid-beta deposition in the damaged cerebral blood vessels of patients with cerebral amyloid angiopathy. These results indicate that overexpression of TGF-beta1 may initiate or promote amyloidogenesis in Alzheimer's disease and in experimental models and so may be a risk factor for developing Alzheimer's disease.

Journal ArticleDOI
TL;DR: A critical role for a proinflammatory cytokine is suggested in the cognitive deficits and associated neuroinflammatory changes that have been documented in neurodegenerative diseases such as Alzheimer disease and AIDS.
Abstract: Inflammation with expression of interleukin 6 (IL-6) in the brain occurs in many neurodegenerative disorders. To better understand the role of IL-6 in such disorders, we examined performance in a learning task in conjunction with molecular and cellular neuropathology in transgenic mice that express IL-6 chronically from astrocytes in the brain. Transgenic mice exhibited dose- and age-related deficits in avoidance learning that closely corresponded with specific progressive neuropathological changes. These results establish a link between the central nervous system expression of IL-6, inflammatory neurodegeneration, and a learning impairment in transgenic mice. They suggest a critical role for a proinflammatory cytokine in the cognitive deficits and associated neuroinflammatory changes that have been documented in neurodegenerative diseases such as Alzheimer disease and AIDS.

Journal ArticleDOI
TL;DR: It is concluded that brain maturity influences the morphologic phenotype of neurodegeneration and that excitotoxic neuronal death in the immature brain is not a uniform event but, rather, a continuum of apoptotic, necrotic, and overlapping morphologies.
Abstract: Glutamate-induced excitotoxicity is a clinically relevant degenerative process that causes selective neuronal death by mechanisms that remain unclear. Cell death is usually classified as apoptotic or necrotic based on biochemical and morphological criteria. Excitotoxic lesions in the adult rat striatum result in neuronal death associated with apoptotic DNA laddering despite a necrotic appearance of neurons ultrastructurally. This suggests that apoptosis and necrosis may not be mutually exclusive modes of cell death. Here, we characterized normal developmental cell death in the newborn rat brain with respect to DNA fragmentation patterns and ultrastructural morphology to establish a standard for apoptosis in the nervous system, and we concluded that it is essentially indistinguishable from apoptosis described in other tissues. We then investigated whether brain maturity could influence the morphology of neuronal death in vivo in the excitotoxically lesioned newborn rat forebrain. Kainic acid induced DNA laddering and death of neurons exhibiting a variety of morphologies, ranging from necrosis to apoptosis. In neurons that were dying by apoptosis, morphologic changes were characterized by a highly ordered sequence of organelle abnormalities, with swelling of endoplasmic reticulum and Golgi vesiculation preceding most nuclear changes and mitochondrial disruption. We concluded that brain maturity influences the morphologic phenotype of neurodegeneration and that excitotoxic neuronal death in the immature brain is not a uniform event but, rather, a continuum of apoptotic, necrotic, and overlapping morphologies. This excitotoxic paradigm might prove useful for analyzing the mechanisms that govern cell death under physiological and pathological conditions.

Journal ArticleDOI
TL;DR: Findings suggest that alteration of NACP metabolism is involved in the pathogenesis of PD, particularly in Lewy body formation, leading to neurodegeneration.

Journal ArticleDOI
TL;DR: The notion that astroglial EAAT2 is affected in AD and abnormal functioning and/or processing of APP might play an important role in this process is supported.
Abstract: Recent studies have shown that deficient functioning of glutamate transporters (GTs) in Alzheimer disease (AD) might lead to neurodegeneration. The main objectives of the present study were to determine which GT subtype is most affected in AD and to asses to what extent altered GT function is associated with abnormal amyloid precursor protein (APP) expression. While EAAT2-immunoreactivity (IR) was decreased in AD frontal cortex, EAAT1- and EAAT3-IR were unaffected; mRNA levels for all 3 GTs were not affected. Decreased EAAT2-IR was associated with decreased GT activity. EAAT2-IR inversely correlated with EAAT2 mRNA levels, suggesting that in AD, GT expression alterations occur due to disturbance at the post-transcriptional level. EAAT2-IR was inversely correlated with APP770 mRNA. In addition, GT activity directly correlated with APP695 mRNA and total APP protein levels, and inversely correlated with APP751/770 mRNA levels. This study supports the notion that astroglial EAAT2 is affected in AD and abnormal functioning and/or processing of APP might play an important role in this process.

Journal ArticleDOI
TL;DR: GT1 cells represent a novel system for studying the molecular mechanisms underlying prion infectivity and subsequent neurodegenerative changes and can be persistently infected with mouse RML prions and conditioned medium from infected cells could transfer prions to uninfected cells.
Abstract: Neuronal death and vacuolation are characteristics of the CNS degeneration found in prion diseases Relatively few cultured cell lines have been identified that can be persistently infected with scrapie prions, and none of these cells show cytopathologic changes reminiscent of prion neuropathology The differentiated neuronal cell line GT1, established from gonadotropin hormone releasing-hormone neurons immortalized by genetically targeted tumorigenesis in transgenic mice (P L Mellon, JJ Windle, P C Goldsmith, C A Padula, J L Roberts, and R I Weiner, Neuron 5:1-10, 1990), was examined for its ability to support prion formation We found that GT1 cells could be persistently infected with mouse RML prions and that conditioned medium from infected cells could transfer prions to uninfected cells In many but not all experiments, a subpopulation of cells showed reduced viability, morphological signs of neurodegeneration and vacuolation, and features of apoptosis Subclones of GT1 cells that were stably transfected with the trk4 gene encoding the high-affinity nerve growth factor (NGF) receptor (GT1-trk) could also be persistently infected NGF increased the viability of the scrapie-infected GT1-trk cells and reduced the morphological and biochemical signs of vacuolation and apoptosis GT1 cells represent a novel system for studying the molecular mechanisms underlying prion infectivity and subsequent neurodegenerative changes

Journal ArticleDOI
TL;DR: Quantitative Western blot analysis of postmortem frontal and temporal lobe tissue demonstrated significantly higher mean levels of p53 and Fas in AD relative to age-matched controls, and suggested that many tau-immunoreactive neuritic processes originate from degenerating (p53) as well as regenerating neurons.

Journal ArticleDOI
TL;DR: It is suggested that “switching off” GluR2 expression in CAI after an ischemic insult is translated into formation of new AMPA receptors lacking the GLUR2 subunit, which increases AMPA-receptor-mediated Ca2+ entry in response to endogenous glutamate and enhances glutamate pathogenicity in this region.
Abstract: Transient, severe forebrain or global ischemia leads to delayed cell death of pyramidal neurons in the hippocampal CA1. The precise molecular mechanisms underlying neuronal cell death after ischemia are as yet unknown. Ca2+ permeable GluR2 lacking alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA) receptors are implicated in the pathogenesis of ischemia-induced degeneration. Global ischemia leads to reduced expression of GluR2 mRNA in vulnerable CAl neurons prior to the delayed cell death. After ischemia, AMPA-receptormediated excitatory postsynaptic currents at the CA1/Schaffer collateral synapse are enhanced and increased in sensitivity to channel blockers selective for Ca2+ permeable AMPA receptors. Moreover, 2,3-dihydroxy-6-nitro-7-sulfamayl-benzo(F)-quinoxaline (NBQX), an AMPA antagonist, protects CA1 neurons against ischemiainduced damage, even when administered 16–24 h after ischemia. These observations suggest that “switching off” GluR2 expression in CAI after an ischemic insult is translated into formation of new AMPA receptors lacking the GluR2 subunit. This change in receptor composition increases AMPA-receptor-mediated Ca2+ entry in response to endogenous glutamate and enhances glutamate pathogenicity in this region (the GluR2 hypothesis). The present study was performed to test whether GluR2 downregulation leads to AMPA-receptor-gated Ca2+ entry into CA1 neurons.

Journal ArticleDOI
TL;DR: Combined intervention using antioxidants, metal chelators, anti-inflammatory drugs and AGE-inhibitors may be a promising neuroprotective strategy.

Journal ArticleDOI
TL;DR: Astroglial and neuronal injury occurs rapidly in H‐I newborn striatum, with early gliodegeneration and glutamate transporter abnormalities possibly contributing to neurodegeneration.
Abstract: The neonatal striatum degenerates after hypoxia-ischemia (H-I). We tested the hypothesis that damage to astrocytes and loss of glutamate transporters accompany striatal neurodegeneration after H-I. Newborn piglets were subjected to 30 minutes of hypoxia (arterial O2 saturation, 30%) and then 7 minutes of airway occlusion (O2 saturation, 5%), producing cardiac arrest, followed by cardiopulmonary resuscitation. Piglets recovered for 24, 48, or 96 hours. At 24 hours, 66% of putaminal neurons were injured, without differing significantly thereafter, but neuronal densities were reduced progressively (21-44%). By DNA nick-end labeling, the number of dying putaminal cells per square millimeter was increased maximally at 24 to 48 hours. Glial fibrillary acidic protein-positive cell body densities were reduced 48 to 55% at 24 to 48 hours but then recovered by 96 hours. Early postischemia, subsets of astrocytes had fragmented DNA; later postischemia, subsets of astrocytes proliferated. By immunocytochemistry, glutamate transporter 1 (GLT1) was lost after ischemia in the astroglial compartment but gained in cells appearing as neurons, whereas neuronal excitatory amino acid carrier 1 (EAAC1) dissipated. By immunoblotting, GLT1 and EAAC1 levels were 85% and 45% of control, respectively, at 24 hours of recovery. Thus, astroglial and neuronal injury occurs rapidly in H-I newborn striatum, with early gliodegeneration and glutamate transporter abnormalities possibly contributing to neurodegeneration.

Journal ArticleDOI
TL;DR: Of the cytokines, IL-1 is identified as a mediator of diverse forms of acute neurodegeneration and has also been implicated in chronic neurological conditions.
Abstract: The last 5 yr have witnessed significant changes in research direction and new discoveries about the mechanisms of neurodegeneration. Earlier studies on neuronal death focused on neurons, neuronal pathways, and neurotransmitters. Now similar interest is directed toward glia and vascular cells, peptides, and inflammatory processes in the brain. This research has already revealed several potential therapeutic targets for the treatment of acute brain damage such as stroke and brain injury. The brain fails to exhibit a classical “inflammatory response,” generally characterized by early invasion of macrophages and leukocytes. Nevertheless, the brain can exhibit many of the hallmarks of inflammation when subjected to ischemia, injury, or infection. Such responses include edema, activation of resident phagocytic cells (microglia), invasion of circulating immune cells, and activation or induction of numerous inflammatory molecules including cyclooxygenase products, kinins, complement, acute phase proteins, and proinflammatory cytokines. Of the cytokines, we have identified IL-1 as a mediator of diverse forms of acute neurodegeneration. IL-1 has also been implicated in chronic neurological conditions.

Journal ArticleDOI
TL;DR: It is concluded that in MJD, as in other polyglutamine repeat diseases, cellular expression of the disease gene is not itself sufficient to cause neuronal degeneration; other cell‐specific factors must be invoked to explain the restricted neuropathology seen inMJD.
Abstract: Machado-Joseph disease (MJD) is one of at least six neurodegenerative diseases caused by expansion of a CAG repeat encoding a polyglutamine tract in the disease protein. To study the molecular mechanism of disease, we isolated both normal and expanded repeat MJD1 cDNAs, and generated antiserum against the recombinant gene product, called ataxin-3. Using this antiserum, we demonstrate that in disease tissue, both the normal and mutant ataxin-3 protein are expressed throughout the body and in all regions of the brain examined, including areas generally spared by disease. In brain, certain regions (the striatum, for example) express ataxin-3 in only a limited subset of neurons. Immunolocalization studies in normal and disease brain, and in transfected cells, indicate that ataxin-3 is predominantly a cytoplasmic protein that localizes to neuronal processes as well. We conclude that in MJD, as in other polyglutamine repeat diseases, cellular expression of the disease gene is not itself sufficient to cause neuronal degeneration; other cell-specific factors must be invoked to explain the restricted neuropathology seen in MJD. The restricted expression of ataxin-3 in certain regions, however, may influence the pattern of neurodegeneration and provide clues to the protein's function.

Journal ArticleDOI
30 Oct 1997-Nature
TL;DR: The features of the interaction between ataxin-1 and LANP, their spatial and temporal patterns of expression, and the colocalization studies indicate that cerebellar LANP is involved in the pathogenesis of SCA1.
Abstract: Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder characterized by ataxia, progressive motor deterioration, and loss of cerebellar Purkinje cells. SCA1 belongs to a growing group of neurodegenerative disorders caused by expansion of CAG repeats, which encode glutamine. Although the proteins containing these repeats are widely expressed, the neurodegeneration in SCA1 and other polyglutamine diseases selectively involves a few neuronal subtypes. The mechanism(s) underlying this neuronal specificity is unknown. Here we show that the cerebellar leucine-rich acidic nuclear protein (LANP) interacts with ataxin-1, the SCA1 gene product. LANP is expressed predominantly in Purkinje cells, the primary site of pathology in SCA1. The interaction between LANP and ataxin-1 is significantly stronger when the number of glutamines is increased. Immunofluorescence studies demonstrate that both LANP and ataxin-1 colocalize in nuclear matrix-associated subnuclear structures. The features of the interaction between ataxin-1 and LANP, their spatial and temporal patterns of expression, and the colocalization studies indicate that cerebellar LANP is involved in the pathogenesis of SCA1.

Journal ArticleDOI
TL;DR: It is suggested that the novel SWS protein plays a role in a signaling mechanism between neurons and glia that regulates glial wrapping during development of the adult brain.
Abstract: Swiss cheese (sws) mutant flies develop normally during larval life but show age-dependent neurodegeneration in the pupa and adult and have reduced life span. In late pupae, glial processes form abnormal, multilayered wrappings around neurons and axons. Degeneration first becomes evident in young flies as apoptosis in single scattered cells in the CNS, but later it becomes severe and widespread. In the adult, the number of glial wrappings increases with age. The sws gene is expressed in neurons in the brain cortex. The conceptual 1425 amino acid protein shows two domains with homology to the regulatory subunits of protein kinase A and to conceptual proteins of yet unknown function in yeast, worm, and human. Sequencing of two sws alleles shows amino acid substitutions in these two conserved domains. It is suggested that the novel SWS protein plays a role in a signaling mechanism between neurons and glia that regulates glial wrapping during development of the adult brain.

Journal ArticleDOI
TL;DR: It is reported that G93A induces a significant loss of mitochondrial membrane potential, an increased sensitivity toward valinomycin and a parallel increase in cytosolic Ca2+ concentration, which are not related to total Cu,ZnSOD content and activity in the cell.

Journal ArticleDOI
TL;DR: Copper-mediated toxicity of APP-Cu(II)/(I) complexes may contribute to neurodegeneration in AD and another neurological disorder, familial amyotrophic lateral sclerosis, supports the view that AD and FALS may be linked through a common mechanism.

Journal ArticleDOI
TL;DR: The hypothesis that mutant SOD induced-neurodegeneration is associated with disturbances of neuronal free radical homeostasis is supported by the results.
Abstract: Mutations in human Cu/Zn superoxide dismutase-1 (SOD) cause approximately 20% of cases of familial amyotrophic lateral sclerosis (FALS). We investigated the mechanism of mutant SOD-induced neuronal degeneration by expressing wild-type and mutant SODs in neuronal cells by means of infection with replication-deficient recombinant adenoviruses. Expression of two FALS-related mutant SODs (A4V and V148G) caused death of differentiated PC12 cells, superior cervical ganglion neurons, and hippocampal pyramidal neurons. Cell death included many features typical of apoptosis. Death could be prevented by copper (Cu2+) chelators, Bcl-2, glutathione, vitamin E, and inhibitors of caspases. Mutant SOD-expressing PC12 cells had higher rates of superoxide (O2-) production under a variety of conditions. The results support the hypothesis that mutant SOD induced-neurodegeneration is associated with disturbances of neuronal free radical homeostasis.

Journal ArticleDOI
TL;DR: It is postulate that NMDA receptor hypoactivity associated with advancing age may have an important contributory role in AD and that a heavier burden of certain adjunctive risk factors may be present in the AD brain that promote the NRHypo state and increase the likelihood that widespread neurodegeneration will occur.
Abstract: Excessive activation of N -methyld-aspartate (NMDA) receptors by endogenous glutamate (Glu) causes excitotoxic neuronal degeneration in acute central nervous system injury syndromes such as stroke and trauma. Early attempts to link NMDA receptor hyper activity (NRHyper) to Alzheimer disease (AD) were stymied by evidence in 3 separate species (mice, rats, and monkeys) that, with advancing age, the NMDA receptor system becomes markedly hypo active. While this would seem to argue against a role for NMDA receptors in AD, we have recently found in animal studies that, when the NMDA receptor system is rendered markedly hypoactive, a disinhibition syndrome is triggered in which low-grade chronic excitotoxic activity (fueled by acetylcholine and Glu) is unleashed that can cause a widespread pattern of neuronal degeneration resembling that seen in AD. Therefore, we postulate that NMDA receptor hypoactivity (NRHypo) associated with advancing age may have an important contributory role in AD and that the main difference between the aging AD brain and the aging "normal" brain is that a heavier burden of certain adjunctive risk factors may be present in the AD brain that promote the NRHypo state and increase the likelihood that widespread neurodegeneration will occur.

Journal ArticleDOI
TL;DR: A body of evidence suggests that the 3-NP model is an improved HD model and may offer a unique system wherein testing of experimental treatments for HD can be carried out across different stages of the disease.