Showing papers on "Motor neuron published in 1998"
TL;DR: The absence of massive motor neuron death at the early stages of the disease indicates that the majority of motor neurons could be rescued after clinical diagnosis, and indicates that mutant SOD1 toxicity is mediated by damage to mitochondria in motor neurons.
Abstract: Amyotrophic lateral sclerosis (ALS) involves motor neuron degeneration, skeletal muscle atrophy, paralysis, and death. Mutations in Cu,Zn superoxide dismutase (SOD1) are one cause of the disease. Mice transgenic for mutated SOD1 develop symptoms and pathology similar to those in human ALS. To understand the disease mechanism, we developed a simple behavioral assay for disease progression in mice. Using this assay, we defined four stages of the disease in mice expressing G93A mutant SOD1. By studying mice with defined disease stages, we tied several pathological features into a coherent sequence of events leading to motor neuron death. We show that onset of the disease involves a sharp decline of muscle strength and a transient explosive increase in vacuoles derived from degenerating mitochondria, but little motor neuron death. Most motor neurons do not die until the terminal stage, approximately 9 weeks after disease onset. These results indicate that mutant SOD1 toxicity is mediated by damage to mitochondria in motor neurons, and this damage triggers the functional decline of motor neurons and the clinical onset of ALS. The absence of massive motor neuron death at the early stages of the disease indicates that the majority of motor neurons could be rescued after clinical diagnosis.
720 citations
TL;DR: It is hypothesized that astrocytic activation may exert a trophic influence on the motor neurons that is insufficiently maintained late in the course of the disease, and agents which inhibit microglia may help to limit disease progression.
Abstract: Transgenic mice that highly over-express a mutated human CuZn superoxide dismutase (SOD1) gene [gly93-->ala; TgN(SOD1-G93A)G1H line] found in some patients with familial ALS (FALS) have been shown to develop motor neuron disease that is characterized by motor neuron loss in the lumbar and cervical spinal regions and a progressive loss of motor activity. The mutant Cu,Zn SOD exhibits essentially normal SOD activity but also generates toxic oxygen radicals as a result of an enhancement of a normally minor peroxidase reaction. Consequently, lipid and protein oxidative damage to the spinal motor neurons occurs and is associated with disease onset and progression. In the present study, we investigated the time course of microglial (major histocompatibility-II antigen immunoreactivity) and astrocytic (glial fibrillary acidic protein immunoreactivity) activation in relation to the course of motor neuron disease in the TgN(SOD1-G93A)G1H FALS mice. Four ages were investigated: 30 days (pre-motor neuron pathology and clinical disease); 60 days (after initiation of pathology, but pre-disease); 100 days (approximately 50% loss of motor neurons and function); and 120 days (near complete hindlimb paralysis). Compared to non-transgenic littermates, the TgN(SOD1-G93A)G1H mice showed significantly increased numbers of activated astrocytes (P < 0.01) at 100 days of age in both the cervical and lumbar spinal cord regions. However, at 120 days of age, the activation lost statistical significance. In contrast, microglial activation was significantly increased several-fold at both 100 and 120 days. We hypothesize that astrocytic activation may exert a trophic influence on the motor neurons that is insufficiently maintained late in the course of the disease. On the other hand, the sustained, intense microglial activation may conceivably contribute to the oxidative stress and damage involved in the disease process. If true, then agents which inhibit microglia may help to limit disease progression.
529 citations
TL;DR: Lhx3 and Lhx4 act in a binary fashion during a brief period in development to specify the trajectory of motor axons from the neural tube.
437 citations
TL;DR: It is concluded that BAX is a critical mediator of naturally occurring death of peripheral and CNS neurons during embryonic life, however, rescue from naturally occurring cell death does not imply that the neurons will develop normal functional capabilities.
Abstract: The proapoptotic molecule BAX is required for death of sympathetic and motor neurons in the setting of trophic factor deprivation. Furthermore, adult Bax−/− mice have more motor neurons than do their wild-type counterparts. These findings raise the possibility that BAX regulates naturally occurring cell death during development in many neuronal populations. To test this idea, we assessed apoptosis using TUNEL labeling in several well-studied neural systems during embryonic and early postnatal development in Bax−/− mice. Remarkably, naturally occurring cell death is virtually eliminated between embryonic day 11.5 (E11.5) and postnatal day 1 (PN1) in most peripheral ganglia, in motor pools in the spinal cord, and in the trigeminal brainstem nuclear complex. Additionally, reduction, although not elimination, of cell death was noted throughout the developing cerebellum, in some layers of the retina, and in the hippocampus. Saving of cells was verified by axon counts of dorsal and ventral roots, as well as facial and optic nerves that revealed 24–35% increases in axon number. Interestingly, many of the supernumerary axons had very small cross-sectional areas, suggesting that the associated neurons are not normal. We conclude that BAX is a critical mediator of naturally occurring death of peripheral and CNS neurons during embryonic life. However, rescue from naturally occurring cell death does not imply that the neurons will develop normal functional capabilities.
433 citations
TL;DR: Evidence is provided that a retinoid-mediated signal provided by one subset of early-born spinal motor neurons imposes a local variation in the number of motor neurons generated at different axial levels and also specifies the identity of a later-born subset ofMotor neurons.
389 citations
TL;DR: The results suggest that the Shh-mediated induction of a single transcription factor, MNR2, is sufficient to direct somatic motor neuron differentiation.
361 citations
TL;DR: The results suggest that peroxynitrite, a strong oxidant formed by the reaction of NO and superoxide, plays an important role in the induction of apoptosis in motor neurons deprived of trophic factors and that BDNF supports motor neuron survival in part by preventing neuronal NOS expression.
Abstract: Primary cultures of rat embryonic motor neurons deprived of brain-derived neurotrophic factor (BDNF) induce neuronal nitric oxide synthase (NOS) within 18 hr. Subsequently, >60% of the neurons undergo apoptosis between 18 and 24 hr after plating. Nitro-l-arginine and nitro-l-arginine methyl ester (l-NAME) prevented motor neuron death induced by trophic factor deprivation. Exogenous generation of nitric oxide at concentrations lower than 100 nm overcame the protection byl-NAME. Manganese tetrakis (4-benzoyl acid) porphyrin, a cell-permeant superoxide scavenger, also prevented nitric oxide-dependent motor neuron death. Motor neurons cultured without trophic support rapidly became immunoreactive for nitrotyrosine when compared with motor neurons incubated with BDNF, l-NAME, or manganese TBAP. Our results suggest that peroxynitrite, a strong oxidant formed by the reaction of NO and superoxide, plays an important role in the induction of apoptosis in motor neurons deprived of trophic factors and that BDNF supports motor neuron survival in part by preventing neuronal NOS expression.
339 citations
TL;DR: It is shown that motor neuron pools and subsets of muscle sensory afferents can be defined by the expression of ETS genes, notably PEA3 and ER81, and that these genes may participate in the development of selective sensory-motor circuits in the spinal cord.
335 citations
TL;DR: The definition of the floor plate domain appears to be defined by the antagonizing activities of Gli2 and Gli3 on Gli1 function, which establishes a regulatory feedback loop triggered by Shh that restricts floor plate cells to the midline.
Abstract: Within the developing vertebrate nervous system, it is not known how progenitor cells interpret the positional information provided by inducing signals or how the domains in which distinct groups of neural cells differentiate are defined. Gli proteins may be involved in these processes. In the frog neural plate, we have previously shown that the zinc finger transcription factor Gli1 is expressed in midline cells and mediates the effects of Shh inducing floor plate differentiation. In contrast, Gli2 and Gli3 are expressed throughout the neural plate except for the midline. Here, it is shown that Gli3 and Shh repress each other whereas Gli2, like Gli1, is a target of Shh signaling. However, only Gli1 can induce the differentiation of floor plate cells. In addition, Gli2 and Gli3 repress the ectopic induction of floor plate cells by Gli1 in co-injection assays and inhibit endogenous floor plate differentiation. The definition of the floor plate domain, therefore, appears to be defined by the antagonizing activities of Gli2 and Gli3 on Gli1 function. Because both Gli1 and Gli2 are induced by Shh, these results establish a regulatory feedback loop triggered by Shh that restricts floor plate cells to the midline. We have also previously shown that the Gli genes induce neuronal differentiation and here it is shown that there is specificity to the types of neurons the Gli proteins induce. Only Gli1 induces Nkx2.1/TTF-1(+) ventral forebrain neurons. Moreover, Gli2 and Gli3 inhibit their differentiation. In contrast, the differentiation of spinal motor neurons can be induced by the two ventrally expressed Gli genes, Gli1 and Gli2, suggesting that Gli2 directly mediates induction of motor neurons by Shh. In addition, Gli3 inhibits motor neuron differentiation by Gli2. Thus, combinatorial Gli function may pattern the neural tube, integrating positional information and cell type differentiation.
257 citations
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04 Sep 1998
TL;DR: Clinical features and differential diagnosis of classical motor neurone disease, including autoimmune aspects of amyotrophic lateral sclerosis, and the management of the early case.
Abstract: Clinical features and differential diagnosis of classical motor neurone disease. Spinal muscular atrophies. The post-polio motor neurone disease. ALS.PD comples on Guam. Natural history. Neurophysiology. The management of the early case. Coping with the disability of established disease. Respiratory function in motor neurone disease. Nutritional support in motor neurone disease. Terminal care. What part can lay MND/ALS associations play in research. Classical pathology. Molecular patholgy: ubiquitin. Neurofilamentous pathology. Epidemiology. Familial motor neurone disease. Gene expression in motor neurone disease. Environmental/gentic interaction. Excitatory amino acids. Metals and free radicals in motor neurone disease. Autoimmune aspects of amyotrophic lateral sclerosis. Trophic factors. Chemical toxins. Viruses and motor neurone disease - the viral hypothesis lives. Neuropeptides - occurrence in motor nerves and relevance to motor neurone disease. Cell culture of motor neurons. Trials in MND.
254 citations
TL;DR: An out‐of‐frame mutation of the mitochondrial DNA‐encoded subunit I of cytochrome c oxidase (COX) was discovered during investigation of a severe isolated muscle COX deficiency in a patient with motor neuron‐like degeneration, suggesting that OXPHOS impairment could play a role in the pathogenesis of some MND cases.
Abstract: An out-of-frame mutation of the mitochondrial DNA-encoded subunit I of cytochrome c oxidase (COX) was discovered during investigation of a severe isolated muscle COX deficiency in a patient with motor neuron-like degeneration. The mutation is a heteroplasmic 5-bp microdeletion located in the 5' end of the COI gene, leading to premature termination of the corresponding translation product. Western blot analysis, immunohisto-chemistry, and single-fiber polymerase chain reaction demonstrated a tight correlation between COX defect, COX I expression, and percentage of mutation. COX subunits II, III, and IV were decreased as well, suggesting a defective assembly of COX holoenzyme. The mutation was associated with a clinical phenotype unusual for a mitochondrial disorder, that is, an isolated motor neuron disease (MND) with some atypical findings, including early onset, preferential involvement of the upper motor neuron, and increased cerebrospinal fluid protein content. MND may arise from impaired scavenging and overproduction of free oxygen radicals, a by-product of oxidative phosphorylation (OXPHOS). Our observation suggests that OXPHOS impairment could play a role in the pathogenesis of some MND cases.
TL;DR: By deleting NF-L, the major neurofilament subunit required for filament assembly, onset and progression of disease caused by familial ALS-linked SOD1 mutant G85R are significantly slowed, while selectivity of mutant-mediated toxicity for motor neurons is reduced.
Abstract: Mutations in superoxide dismutase 1 (SOD1), the only proven cause of amyotrophic lateral sclerosis (ALS), provoke disease through an unidentified toxic property. Neurofilament aggregates are pathologic hallmarks of both sporadic and SOD1-mediated familial ALS. By deleting NF-L, the major neurofilament subunit required for filament assembly, onset and progression of disease caused by familial ALS-linked SOD1 mutant G85R are significantly slowed, while selectivity of mutant-mediated toxicity for motor neurons is reduced. In NF-L-deleted animals, levels of the two remaining neurofilament subunits, NF-M and NF-H, are markedly reduced in axons but are elevated in motor neuron cell bodies. Thus, while neither perikaryal nor axonal neurofilaments are essential for SOD1-mediated disease, the absence of assembled neurofilaments both diminishes selective vulnerability and slows SOD1G85R mutant-mediated toxicity to motor neurons.
TL;DR: In this article, the role of neurofilaments in motor neuron disease caused by superoxide dismutase (SOD1) mutations was investigated, where transgenic mice expressing a amyotrophic lateral sclerosis-linked SOD1 mutant (sOD1G37R) were mated with transgen mice expressing human neurofilament heavy (NF-H) subunits.
Abstract: To investigate the role of neurofilaments in motor neuron disease caused by superoxide dismutase (SOD1) mutations, transgenic mice expressing a amyotrophic lateral sclerosis-linked SOD1 mutant (SOD1G37R) were mated with transgenic mice expressing human neurofilament heavy (NF-H) subunits. Unexpectedly, expression of human NF-H transgenes increased by up to 65%, the mean lifespan of SOD1G37R mice. Microscopic examination corroborated the protective effect of NF-H protein against SOD1 toxicity. Although massive neurodegeneration occurred in 1-yr-old mice expressing SOD1G37R alone, spinal root axons and motor neurons were remarkably spared in doubly SOD1G37R;NF-H-transgenic littermates.
01 Jan 1998
TL;DR: Although massive neurodegeneration occurred in 1-yr-old mice expressing S OD1(G37R) alone, spinal root axons and motor neurons were remarkably spared in doubly SOD1( G37R);NF-H-transgenic littermates.
Abstract: To investigate the role of neurofilaments in motor neuron disease caused by superoxide dismutase (SOD1) mutations, transgenic mice expressing a amyotrophic lateral sclerosis-linked SOD1 mutant (SOD1 G37R ) were mated with transgenic mice expressing human neurofilament heavy (NF-H) subunits. Unexpectedly, expression of human NF-H transgenes increased by up to 65%, the mean lifespan of SOD1 G37R mice. Microscopic examination corroborated the protective effect of NF-H protein against SOD1 toxicity. Although massive neurodegeneration occurred in 1-yr-old mice expressing SOD1 G37R alone, spinal root axons and motor neurons were remarkably spared in doubly SOD1 G37R ;NF-H-
TL;DR: In vivo grafting studies suggest that the generation of motor neuron subtypes in the developing spinal cord involves the integration of distinct rostrocaudal and dorsoventral patterning signals that derive, respectively, from paraxial and axial mesodermal cell groups.
Abstract: The generation of distinct classes of motor neurons is an early step in the control of vertebrate motor behavior. To study the interactions that control the generation of motor neuron subclasses in the developing avian spinal cord we performed in vivo grafting studies in which either the neural tube or flanking mesoderm were displaced between thoracic and brachial levels. The positional identity of neural tube cells and motor neuron subtype identity was assessed by Hox and LIM homeodomain protein expression. Our results show that the rostrocaudal identity of neural cells is plastic at the time of neural tube closure and is sensitive to positionally restricted signals from the paraxial mesoderm. Such paraxial mesodermal signals appear to control the rostrocaudal identity of neural tube cells and the columnar subtype identity of motor neurons. These results suggest that the generation of motor neuron subtypes in the developing spinal cord involves the integration of distinct rostrocaudal and dorsoventral patterning signals that derive, respectively, from paraxial and axial mesodermal cell groups.
TL;DR: An increase in spinal cord lipid peroxidation is demonstrated in the FALS transgenic model, which precedes the onset of ultrastructural or clinical motor neuron disease, and further support a role of oxygen radical‐mediated motor neuronal injury in the pathogenesis of FALS and the potential benefits of antioxidant therapy.
Abstract: Transgenic mice that overexpress a mutated human CuZn superoxide dismutase (SOD1) gene (gly93-->ala) found in some patients with familial ALS (FALS) have been shown to develop motor neuron disease, as evidenced by motor neuron loss in the lumbar and cervical spinal regions and a progressive loss of voluntary motor activity. The mutant Cu,Zn SOD exhibits essentially normal dismutase activity, but in addition, generates toxic oxygen radicals as a result of an enhancement of a normally minor peroxidase reaction. In view of the likelihood that the manifestation of motor neuron disease in the FALS transgenic mice involves an oxidative injury mechanism, the present study sought to examine the extent of lipid peroxidative damage in the spinal cords of the TgN(SOD1-G93A)G1H mice over their life span compared to nontransgenic littermates or transgenic mice that overexpress the wild-type human Cu,Zn SOD (TgN(SOD1)N29). Lipid peroxidation was investigated in terms of changes in vitamin E and malondialdehyde (MDA) levels measured by HPLC methods and by MDA-protein adduct immunoreactivity. Four ages were investigated: 30 days (pre-motor neuron pathology and clinical disease); 60 days (after initiation of pathology, but predisease); 100 days (approximately 50% loss of motor neurons and function); and 120 days (near complete hindlimb paralysis). Compared to nontransgenic mice, the TgN(SOD1-G93A)G1H mice showed blunted accumulation of spinal cord vitamin E and higher levels of MDA (P < 0.05 at 30 and 60 days) over the 30-120 day time span. In the TgN(SOD1)N29 mice, levels of MDA at age 120 days were significantly lower than in either the TgN(SOD1-G93A)G1H or nontransgenic mice. MDA-protein adduct immunoreactivity was also significantly increased in the lumbar spinal cord at age 30, 100, and 120 days, and in the cervical cord at 100 and 120 days. The results clearly demonstrate an increase in spinal cord lipid peroxidation in the FALS transgenic model, which precedes the onset of ultrastructural or clinical motor neuron disease. However, the greatest intensity of actual motor neuronal lipid peroxidative injury is associated with the active phase of disease progression. These findings further support a role of oxygen radical-mediated motor neuronal injury in the pathogenesis of FALS and the potential benefits of antioxidant therapy.
TL;DR: The observed facilitation of motoneurons during contraction of contralateral muscles might involve a transcallosal pathway modulating the excitability of one cortex when the other is activated.
Abstract: The size of compound motor evoked potentials (cMEPs) to transcranial magnetic stimulation of the motor cortex was measured in the relaxed first dorsal interosseous muscle of the nondominant hand (ndFDI) during different levels of voluntary contraction in the homonymous muscle of the dominant hand (dFDI). cMEP responses in the ndFDI became larger when the dFDI was contracted to forces ranging 10-70% of maximum voluntary contraction. Variability in the amplitude of the cMEP responses in ndFDI decreased when dFDI was contracted. Comparison with cMEPs to spinal cord stimulation suggested a large component of the facilitation was occurring at a cortical level. The amplitude of cMEP responses in ndFDI also increased when the tibialis anterior muscle of the leg on the contralateral side was contracted. The observed facilitation of motoneurons during contraction of contralateral muscles might involve a transcallosal pathway modulating the excitability of one cortex when the other is activated.
TL;DR: The results suggest that motor neurons are potential loci for storage of the memory in sensitization and emphasize the importance of plasticity at sensory–motor synapses, consistent with the idea that there are multiple sites of Plasticity distributed throughout the nervous system.
Abstract: Although in vitro analyses of long-term changes in the sensorimotor connection of Aplysia have been used extensively to understand long-term sensitization, relatively little is known about the ways in which the connection is modified by learning in vivo . Moreover, sites other than the sensory neurons might be modified as well. In this paper, several different biophysical properties of sensory neurons, motor neurons, and LPl17, an identified interneuron, were examined. Membrane properties of sensory neurons, which were expressed as increased excitability and increased spike afterdepolarization, were affected by the training. The biophysical properties of motor neurons also were affected by training, resulting in hyperpolarization of the resting membrane potential and a decrease in spike threshold. These results suggest that motor neurons are potential loci for storage of the memory in sensitization. The strength of the connection between sensory and motor neurons was affected by the training, although the connection between LPl17 and the motor neuron was unaffected. Biophysical properties of LPl17 were unaffected by training. The results emphasize the importance of plasticity at sensory–motor synapses and are consistent with the idea that there are multiple sites of plasticity distributed throughout the nervous system.
TL;DR: This work detects receptor activation in the spinal cord in a pattern that indicates that the receptor functions in the maturation of limb-innervating motor neurons and indicates that RXR is a critical bona fide receptor in the developing spinal cord.
Abstract: Retinoids regulate gene expression through the action of retinoic acid receptors (RARs) and retinoid-X receptors (RXRs), which both belong to the family of nuclear hormone receptors1,2. Retinoids are of fundamental importance during development2, but it has been difficult to assess the distribution of ligand-activated receptors in vivo. This is particularly the case for RXR, which is a critical unliganded auxiliary protein for several nuclear receptors, including RAR1, but its ligand-activated role in vivo remains uncertain. Here we describe an assay in transgenic mice, based on the expression of an effector fusion protein linking the ligand-binding domain of either RXR or RAR to the yeast Gal4 DNA-binding domain, and the in situ detection of ligand-activated effector proteins by using an inducible transgenic lacZ reporter gene. We detect receptor activation in the spinal cord in a pattern that indicates that the receptor functions in the maturation of limb-innervating motor neurons. Our results reveal a specific activation pattern of Gal4–RXR which indicates that RXR is a critical bona fide receptor in the developing spinal cord.
TL;DR: The data suggest that the SOD-1 mutation is associated with impaired calcium homeostasis in motoneurons in vivo, with increased likelihood of degeneration associated with higher levels of intracellular calcium and lower to absent levels of calbindin-D28K and/or parvalbumin, and decreased likelihood of deterioration associated with minimally changed calcium.
Abstract: Transgenic mice with Cu,Zn superoxide dismutase (SOD-1) mutations provide a unique model to examine altered Ca homeostasis in selectively vulnerable and resistant motoneurons. In degenerating spinal motoneurons of G93 A SOD-1 mice, developing vacuoles were filled with calcium, while calcium was gradually depleted from the cytoplasm and intact mitochondria. In oculomotor neurons, no degenerative changes, vacuolization, or increased calcium were noted. Motor axon terminals of interosseus muscle gradually degenerated and intracellular calcium was depleted. Oculomotor terminals of mutant SOD-1 mice were smaller and exhibited no degenerative changes, but did exhibit unique membrane-enclosed organelles containing calcium. Spinal motoneurons of SOD-1 mice were shown to have fewer calcium binding proteins, such as parvalbumin, compared with oculomotor neurons. These data suggest that the SOD-1 mutation is associated with impaired calcium homeostasis in motoneurons in vivo, with increased likelihood of degeneration associated with higher levels of intracellular calcium and lower to absent levels of calbindin-D28K and/or parvalbumin, and decreased likelihood of degeneration associated with minimally changed calcium and ample calbindin-D28K and/or parvalbumin.
TL;DR: The distribution and density of EAAT2 in the motor cortex and spinal cord of MND cases compared with neurologically normal controls was compared and indicates that glutamate transporter pathology in motor neuron disease may be a more complex phenomenon than previously recognized.
Abstract: Emerging evidence suggests that a disturbance of the glutamate neurotransmitter system may be a contributory factor to motor neuron injury in motor neuron disease. Previous autoradiographic and immunoblotting studies have suggested that there may be reduced expression of glutamate transporter proteins in pathologically affected areas of the CNS in motor neuron disease. This study further explores the possible alteration in expression of the excitatory amino acid transporter protein EAAT2 in MND, by examining the protein expression in situ, in frozen sections, using immunohistochemistry. The aim of the study was to compare the distribution and density of EAAT2 in the motor cortex and spinal cord of MND cases (n = 16) compared with neurologically normal controls (n = 12), matched for relevant parameters. A novel, previously characterized, monoclonal antibody to EAAT2 was employed. EAAT2 immunoreactivity in motor neuron disease and control cases was compared using relative optical density measurements generated by computerized image analysis. In the motor cortex, EAAT2 immunoreactivity was laminated comprising a superficial intense band (corresponding to layers 1 and 2); a paler middle band (layer 3 and part of 5) and a more intense deep layer (layers 5 and 6). In the spinal cord, the ventral horn showed strong immunoreactivity with dense perisomatic staining around motor neuron cell bodies, the substantia gelatinosa showed moderate diffuse staining and the intermediate spinal laminae showed weak staining. This general pattern of immunoreactivity was preserved in the motor neuron disease cases. However, in the motor neuron disease cases compared with controls, the optical density values for EAAT2 immunoreactivity were significantly reduced in all grey matter regions of the lumbar spinal cord (P < 0.001) and were increased in the middle laminae of the motor cortex (P < 0.05). This study indicates that glutamate transporter pathology in motor neuron disease may be a more complex phenomenon than previously recognized.
TL;DR: Spectroscopic changes in the motor cortices of patients with ALS correspond with a reduction in Levels of NAA and an elevation in levels of choline and inositol compounds, so the release of these compounds may be related to membrane disorders.
Abstract: Objectives To determine the motor cortex degeneration in patients with amyotrophic lateral sclerosis (ALS) using proton magnetic resonance spectroscopy, and to prove that proton magnetic resonance spectroscopy is suited to monitor the course of disease with follow-up examinations Materials and Methods We studied 33 patients with ALS whose conditions were diagnosed according to the El Escorial World Federation of Neurology criteria Nine patients with ALS were followed up for up to 2 years The control group included 20 healthy volunteers and 4 patients with multifocal motor neuropathy Proton magnetic resonance spectroscopy determined levels of the brain metabolites N -acetylaspartate (NAA), choline, inositol-containing compounds, glutamate/glutamine, and phosphocreatine Results Patients with ALS showed a significant reduction in the NAA-choline ( P P P P P 1 and T 2 relaxation times were observed Patients with multifocal motor neuropathy showed normal metabolic ratios Progressive alterations in affected metabolite ratios could be documented in the follow-up examinations Conclusions Spectroscopic changes in the motor cortices of patients with ALS correspond with a reduction in levels of NAA and an elevation in levels of choline and inositol compounds Since NAA is exclusively expressed in neurons, the observed decrease of NAA reflects neuronal loss or dysfunction Inositol and choline are associated with plasma membrane metabolism, so the release of these compounds may be related to membrane disorders
TL;DR: Double-strand breaks in genomic DNA and induction of three caspases were demonstrated and indicate that motor neuron death in the spinal cord after transient ischemia is profoundly associated with activation of apoptotic processes.
Abstract: Background and Purpose —Some neuronal subpopulations are especially vulnerable to ischemic injury. In the spinal cord, large motor neurons are vulnerable to ischemia and are selectively lost after transient ischemia. However, the mechanisms of the neuronal loss have been uncertain. We hypothesized that spinal motor neurons might be lost by apoptosis and investigated a possible mechanism of neuronal death by detection of double-strand breaks in genomic DNA and immunohistochemical analysis for caspases, ie, interleukin-1β converting enzyme (ICE), Nedd-2 , and CPP32.
Methods —We used a rabbit spinal cord ischemia model created with a balloon catheter. The spinal cord was removed at 8 hours, 1, 2, or 7 days after 15 minutes of transient ischemia, and histological changes were studied with hematoxylin-eosin staining. To detect double-strand breaks in DNA, a staining with terminal deoxynucleotidyl transferase–mediated dUTP-biotin in situ nick end labeling (TUNEL) was performed. Furthermore, expression of ICE, Nedd-2 , and CPP32 was investigated by Western blotting and immunohistochemical analysis.
Results —Motor neurons were selectively lost at 7 days after transient ischemia. TUNEL study demonstrated that no cells were positively labeled until 1 day after ischemia, but nuclei of some motor neurons were positively labeled at 2 days. Western blot analysis revealed no immunoreactivity for ICE and slight immunoreactivities for Nedd-2 and CPP32 in the sham-operated spinal cords. However, immunoreactivity became apparent at 8 hours after transient ischemia, decreased at 1 day, and returned to baseline level at 2 days. Immunohistochemical analysis demonstrated that motor neurons were responsible for induction of those caspases.
Conclusions —Double-strand breaks in genomic DNA and induction of three caspases were demonstrated. These results indicate that motor neuron death in the spinal cord after transient ischemia is profoundly associated with activation of apoptotic processes.
TL;DR: It is proposed that a decreased expression of sema III/coll-1, one of the major ligands for neuropilin- 1, during peripheral nerve regeneration is an important molecular event that is part of the adaptive response related to the success of regenerative neurite outgrowth occurring following peripheral nerve injury.
TL;DR: It is suggested that anterogradely transported mutant SOD1 may act locally to damage motor axons of the sciatic nerve.
TL;DR: The view that at least part of NMDA receptor-dependent arborization of motor neuron dendrites is mediated by the local production of NO within the developing spinal cord is supported.
Abstract: Nitric oxide (NO) has been implicated in the establishment of precise synaptic connectivity throughout the neuroaxis in several species. To determine the contribution of NO to NMDA receptor-dependent dendritic growth in motor neurons, we administered the NMDA antagonist MK-801 to wild-type mice and neuronal nitric oxide synthase (nNOS) knock-out mice between postnatal days 7 and 14. Compared to saline-treated wild-type animals the number of dendritic bifurcations was significantly reduced in nNOS knock-out animals and MK-801-treated wild-type animals. There was no significant difference in dendritic bifurcation between MK-801-treated wild-type, MK-801-treated nNOS knock-out, and saline-treated nNOS knock-out animals, suggesting that nNOS knock-out and NMDA receptor block had similar effects. The path of the longest dendrite and the number of primary dendrites was the same in all treatment groups, indicating an effect specific to bifurcation. Sholl analysis revealed that differences in bifurcation numbers occurred between 160 and 320 micrometers from the cell body, the distance at which second, third, and fourth order dendrites are most prevalent. Dendrite order analyses confirmed a significant reduction in numbers, but not lengths, of third and fourth order dendrites in nNOS knock-out and drug-treatment groups. Finally, immunohistochemical examination of the developing spinal cord indicated that NMDA receptors and nNOS are colocalized within interneurons surrounding the motor neuron pool. These results support the view that at least part of NMDA receptor-dependent arborization of motor neuron dendrites is mediated by the local production of NO within the developing spinal cord.
TL;DR: Muscle specific transcription factors of the helix-loop-helix family such as myoD and myogenin could be important for regulating genes related to metabolic profile and fibre size/strength, while their role in determining myosin heavy chain expression and classical fibre type is more uncertain.
Abstract: Contractile phenotype of muscle fibres is strongly influenced by hormones, stretch and influences from the motor neurones, although cell lineage probably also plays a role. Motor neurones can affect muscle fibres by releasing neurotrophic substances and by evoking electrical activity in the muscle. For regulating contractile properties such as speed, strength and endurance it has been demonstrated that electrical activity is crucial, while the role of putative neurotrophic substances remains unclear. The signal to change is coded in the pattern of electrical activity. Thus, high amounts of activity lead to slow shortening velocity and myosin heavy chains, while low amounts of activity lead to a fast phenotype. For regulation of twitch duration frequency also plays a role, and for preventing atrophy in denervated muscles high frequency seems to be beneficial, particularly in fast muscles. Little is known about the excitation-adaptation pathway linking action potentials to expression of genes that are relevant for contractile properties. Muscle specific transcription factors of the helix-loop-helix family such as myoD and myogenin could be important for regulating genes related to metabolic profile and fibre size/strength, while their role in determining myosin heavy chain expression and classical fibre type is more uncertain.
TL;DR: The identical timing of motor neuron and interneuron degeneration in this model of ALS strongly suggests that degenerationIn the spinal cord of patients with ALS is not specifically directed at motor neurons, but rather more generally at several populations of neurons in the spinal Cord.
Abstract: Transgenic mice with a G86R mutation in the mouse superoxide dismutase (SOD-1) gene, which corresponds to a mutation observed in familial amyotrophic lateral sclerosis (ALS), display progressive motor dysfunction leading to paralysis and premature death. In endstage SOD-1 transgenic mice, there is marked loss of spinal motor neurons and interneurons, accumulation of phosphorylated neurofilament inclusions, and reactive astrocytosis. The present study details the time course and ultrastructural appearance of these pathologic changes and correlates the timing of these events with the behavioral symptoms. There is no significant reduction in the number of total neurons, motor neurons, or interneurons in the ventral spinal cord of presymptomatic mice, as compared to age-matched control mice. In contrast, there is a significant reduction in the number of total neurons (−23.5%), motor neurons (-28.9%), and interneurons (-23.5%) in symptomatic SOD-1 transgenic mice. This neuron loss correlates temporally with the onset of reactive astrocytosis and the appearance of phosphorylated neurofilament inclusions. The identical timing of motor neuron and interneuron degeneration in this model of ALS strongly suggests that degeneration in the spinal cord of patients with ALS is not specifically directed at motor neurons, but rather more generally at several populations of neurons in the spinal cord. In addition, the late onset and rapid progression of neuron loss suggest that a toxic property is accumulating while the SOD-1 transgenic mice are presymptomatic, and that this toxic property must reach a threshold level before the onset of neuronal degeneration. J. Comp. Neurol. 391:64–77, 1998. © 1998 Wiley-Liss, Inc.
TL;DR: ECR and FCR co-contraction in writer's cramp may be a compensatory process under voluntary control and is produced by abnormal synchronization of presynaptic inputs to antagonist motor neuron pools.
Abstract: The aim of this study was to examine the pathophysiological mechanisms underlying co-contraction in patients with dystonia (n = 6) and writer's cramp (n = 5). Multi-unit needle and surface EMGs were recorded from extensor carpi radialis (ECR) and flexor carpi radialis (FCR) muscles during motor tasks that elicited dystonia or writer's cramp. The EMGs from ECR and FCR were recorded simultaneously and analysed using cross-correlation analysis. Similar recordings were obtained from healthy age- and sex-matched control subjects (n = 8). Despite co-contraction of the muscles, cross-correlograms from the healthy subjects did not reveal evidence of motor unit synchronization. Cross-correlograms from the dystonic subjects revealed a central peak with a median duration of 37 ms, indicating broad-peak motor unit synchronization. Cross-correlograms from patients with writer's cramp were either flat or modulated by a 11-12-Hz tremor. Frequency-domain analysis of ECR and FCR EMGs demonstrated significant coherence in the patients with dystonia and writer's cramp. These results indicate that co-contraction in dystonia is neurophysiologically distinct from voluntary co-contraction and is produced by abnormal synchronization of presynaptic inputs to antagonist motor neuron pools. ECR and FCR co-contraction in writer's cramp may be a compensatory process under voluntary control.
TL;DR: It is proposed that spinal motoneurons can be influenced by IFN-gamma and recognized by cytotoxic CD8+ T-cells, and could be of relevance in the search for pathogenetic mechanisms in motoneuron-specific diseases, such as ALS.