Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Current research evidence suggests that genetic factors, oxidative stress and glutamatergic toxicity, with damage to critical target proteins and organelles, may be important contributory factors to motor neuron injury in amyotrophic lateral sclerosis (ALS). Various molecular and neurochemical features of human motor neurons may render this cell group differentially vulnerable to such insults. Motor neurons are large cells with long axonal processes which lead to requirements for a high level of mitochondrial activity and a high neurofilament content compared to other neuronal groups. The lack of calcium buffering proteins parvalbumin and calbindin D28k and the low expression of the GluR2 AMPA receptor subunit may render human motor neurons particularly vulnerable to calcium toxicity following glutamate receptor activation. Motor neurons also have a high perisomatic expression of the glutamate transporter protein EAAT2 and a very high expression of the cytosolic free radical scavenging enzyme Cu/Zn superoxide dismutase (SOD1) which may render this cell group vulnerable in the face of genetic or post-translational alterations interfering with the function of these proteins. More detailed characterisation of the molecular features of human motor neurons in the future may allow the strategic development of better neuroprotective therapies for the benefit of patients afflicted by ALS.
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PMID:Molecular factors underlying selective vulnerability of motor neurons to neurodegeneration in amyotrophic lateral sclerosis. 1079 83

Recent reports challenge the hypothesis that expression of calcium binding proteins contributes to the greater resistance of some motoneurons to degeneration in amyotrophic lateral sclerosis (ALS). We therefore re-examined, using immunohistochemistry, the expression of calbindin, calretinin and parvalbumin in vulnerable (hypoglossal, XII; and cervical spinal) and resistant (oculomotor, III) motoneurons of adult rats. Calbindin immunoreactivity was lacking in motor nuclei but strong in the dorsal horn. Calretinin was expressed in spinal, but not III or XII, motoneurons. Parvalbumin immunoreactivity, tested with a polyclonal antibody, was intense in spinal and III, but not XII, motoneurons; however, no staining in the ventral horn was observed with a monoclonal antibody. Differential expression of calretinin and parvalbumin within vulnerable motoneurons suggests that immunoreactivity for these proteins is not a reliable marker for resistance to degeneration in ALS.
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PMID:Calcium binding proteins in motoneurons at low and high risk for degeneration in ALS. 1105 92

Degeneration of both motoneurons and interneurons has been previously observed in amyotrophic lateral sclerosis. It is unclear whether interneuronal loss is due to an intrinsic neuronal defect or if it occurs secondary to loss of their target motoneurons. We have examined the target dependence of interneurons, their survival and alterations in the expression of the calcium binding protein, calbindin-D28k (CB), in the ventral horn of the rat lumbar cord after extensive motoneuron degeneration was induced by unilateral rhizotomy of spinal nerves L2-L6 at postnatal day 3 (P3). Counts of Nissl-stained cells at P21 revealed no significant interneuronal death despite loss of 80% of their target motoneurons. At P6, some motoneurons transiently expressed CB on the operated side compared to the control side. Since most of these cells are destined to die, this transiently increased CB expression may represent an abortive attempt by the axotomised motoneurons to buffer the neurotoxic consequences of high intracellular calcium. In contrast, there was a time-dependent decrease in CB expression in ventral horn interneurons, with only 35% of putative Renshaw cells expressing CB by P21. These results indicate that neonatal interneurons are capable of surviving the loss of their motoneuron targets, but alter their phenotype as indicated by functional alterations in calcium-binding proteins.
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PMID:Interneuronal survival and calbindin-D28k expression following motoneuron degeneration. 1109 Aug 63

There are several incurable diseases of motor neuron degeneration, including amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, hereditary spastic hemiplegia, spinal muscular atrophy, and bulbospinal atrophy. Advances in gene transfer techniques coupled with new insights into molecular pathology have opened promising avenues for gene therapy aimed at halting disease progression. Nonviral preparations and recombinant adenoviruses, adeno-associated viruses, herpesviruses, and lentiviruses may ultimately transduce sufficient numbers of cerebral, brainstem, and spinal cord neurons for therapeutic applications. This could be accomplished by direct injection, transduction of lower motor neurons via retrograde transport after intramuscular injection, or cell-based therapies. Studies using transgenic mice expressing mutant superoxide dismutase 1 (SOD1), a model for one form of ALS, established that several proteins were neuroprotective, including calbindin, bcl-2, and growth factors. These same molecules promoted neuronal survival in other injury models, suggesting general applicability to all forms of ALS. Potentially correctable genetic lesions have also been identified for hereditary spastic hemiplegia, bulbospinal atrophy, and spinal muscular atrophy. Finally, it may be possible to repopulate lost corticospinal and lower motor neurons by transplanting stem cells or stimulating native progenitor populations. The challenge ahead is to translate these basic science breakthroughs into workable clinical practice.
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PMID:Gene therapy for amyotrophic lateral sclerosis and other motor neuron diseases. 1109 37

A qualitative immunohistochemical study was performed on calcineurin A- and calbindin-positive neurons in the spinal cord of transgenic mice, an animal model of amyotrophic lateral sclerosis, carrying the G93A mutation of the Cu/Zn-superoxide dismutase gene. The results show that calcineurin A-immunoreactive motoneurons are affected by the neurodegenerative process; in contrast, calbindin-positive cells are selectively spared. The findings suggest that calcineurin plays a role as an accessory factor responsible for selective vulnerability in the neurodegenerative process of amyotrophic lateral sclerosis.
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PMID:Calcineurin A and calbindin immunoreactivity in the spinal cord of G93A superoxide dismutase transgenic mice. 1116 10

Motor neuron dysfunction and loss in amyotrophic lateral sclerosis (ALS) have been attributed to several different mechanisms, including increased intracellular calcium, glutamate excitotoxicity, oxidative stress and free radical damage, mitochondrial dysfunction, and neurofilament aggregation and dysfunction of transport mechanisms. These alterations are not mutually exclusive, and increased calcium could be a common denominator. Furthermore, the selective vulnerability of spinal motor neurons and the relative sparing of eye motor neurons represent striking features of both sporadic and familial ALS. Here we review the evidence that calcium homeostasis is altered in ALS, and that low levels of the calcium binding proteins parvalbumin and calbindin-D28K contribute to selective vulnerability by decreasing the ability of motor neurons to handle an increased calcium load, with cell injury and death as the consequence.
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PMID:Calcium: the Darth Vader of ALS. 1146 25

Excitotoxicity, which is mediated by the excessive activation of glutamate receptors, has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). There is substantial information about the distribution and function of ionotropic glutamate receptors in the spinal cord, although the role of metabotropic glutamate receptors (mGluRs) is poorly understood in this region of the brain, particularly under pathological conditions. We used immunocytochemistry to study the general distribution of group I and group II mGluR immunoreactivity in the human spinal cord, as well as the cell-specific expression of these receptors. We also investigated whether mGluR expression was altered in the spinal cord of patients with sporadic and familial ALS. Immunocytochemical analysis of control human spinal cord demonstrated that mGluR1alpha and mGluR5 (group I mGluRs) were highly represented in neuronal cells throughout the spinal cord. mGluR1alpha showed the highest relative level of expression in ventral horn neurons (laminae VIII and IX), whereas intense mGluR5 immunoreactivity was observed within the dorsal horn (superficial laminae I and II). Group II mGluRs (mGluR2/3) immunoreactivity was mainly concentrated in the inner part of the lamina II. With respect to specific neuronal populations, mGluR2/3 and mGluR5 appeared to be most frequently expressed in calbindin-containing and calretinin-containing cells, respectively. In control spinal cord only sparse astrocytes showed a weak to moderate mGluR immunoreactivity. Regional differences in immunoreactivity were apparent in ALS compared to control. In particular, mGluR expression was increased in reactive glial cells in both gray (ventral horn) and white matter of ALS spinal cord. Upregulation of mGluRs in reactive astrocytes may represent a critical mechanism for modulation of glial function and changes in glial-neuronal communication in the course of neurodegenerative diseases.
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PMID:Immunohistochemical localization of group I and II metabotropic glutamate receptors in control and amyotrophic lateral sclerosis human spinal cord: upregulation in reactive astrocytes. 1167 16

Following nerve injury in neonatal rats, a large proportion of motoneurons die, possibly as a consequence of an increase in vulnerability to the excitotoxic effects of glutamate. Calcium-dependent glutamate excitotoxicity is thought to play a significant role not only in injury-induced motoneuron death, but also in motoneuron degeneration in diseases such as amyotrophic lateral sclerosis (ALS). Motoneurons are particularly vulnerable to calcium influx following glutamate receptor activation, as they lack a number of calcium binding proteins, such as calbindin-D(28k) and parvalbumin. Therefore, it is possible that increasing the ability of motoneurons to buffer intracellular calcium may protect them from cell death and prevent the decline in motor function that usually occurs as a consequence of motoneuron loss. In this study we have tested this possibility by examining the effect of neonatal axotomy on motoneuron survival and muscle force production in normal and transgenic mice that over-express parvalbumin in their motoneurons.The sciatic nerve was crushed in one hindlimb of new-born transgenic and wildtype mice. The effect on motoneuron survival was assessed 8 weeks later by retrograde labelling of motoneurons innervating the tibialis anterior muscle. Following nerve injury in wildtype mice, only 20.2% (+/-2.2, S.E.M.; n=4) of injured motoneurons survive long term compared with 47.2% (+/-4.4, S.E.M.; n=4) in parvalbumin over-expressing mice. Surprisingly, this dramatic increase in motoneuron survival was not reflected in a significant improvement in muscle function, since 8 weeks after injury there was no improvement in either maximal twitch and tetanic force, or muscle weights.Thus, inducing spinal motoneurons to express parvalbumin protects a large proportion of motoneurons from injury-induced cell death, but this is not sufficient to restore muscle function.
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PMID:Over-expression of parvalbumin in transgenic mice rescues motoneurons from injury-induced cell death. 1469 53

Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a progressive neurodegenerative disease affecting the indigenous Chamorro population of Guam. Neuropathologically, PDC is characterized by neuronal loss in the substantia nigra pars compacta with severe widespread neurofibrillary tangles (NFTs) similar to those observed in Alzheimer's disease (AD), and is thus considered a tauopathy. Following reports of alpha-synuclein pathology in PDC patients of Guam, PDC has also been neuropathologically classified as a synucleinopathy. Recently, the presence of alpha-synuclein-positive bodies has been reported in the cerebellum of some patients with Parkinson's disease (PD), diffuse Lewy body disease (DLBD), or multiple system atrophy (MSA). Using immunohistochemical techniques, we investigated the deposition of alpha-synuclein in the cerebellum of Guamanian PDC patients. Numerous alpha-synuclein-immunoreactive spherical structures were found in the molecular layer of the cerebellum of 63.6% of PDC patients. These structures were only seen in patients showing alpha-synuclein pathology in the amygdala. The average density of alpha-synuclein-immunoreactive structures in the cerebellum of Guamanian PDC patients was almost an order of magnitude higher than in non-Guamanian PD patients, and this alpha-synuclein pathology was much more pronounced in the hemisphere than in the vermis. In addition, double immunohistochemistry revealed that cerebellar alpha-synuclein is co-localized with the neuronal marker calbindin and with glial-fibrillary acidic protein, suggesting the involvement of Purkinje cells and Bergmann glia. These findings demonstrate that the alpha-synuclein pathology in PDC of Guam affects not only the amygdala, but also the cerebellum, where it appears to involve both Purkinje cells and specialized astrocytes.
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PMID:Occurrence of alpha-synuclein pathology in the cerebellum of Guamanian patients with parkinsonism-dementia complex. 1502 81

Neuroimaging and neuropsychological studies have revealed that the primary motor cortex (PMC) and the extramotor cortical areas are functionally abnormal in motor neuron disease (MND, amyotrophic lateral sclerosis), but the nature of the cortical lesions that underlie these changes is poorly understood. In particular, there have been few attempts to quantify neuronal loss in the PMC and in other cortical areas in MND. We used SMI-32, an antibody against an epitope on non-phosphorylated neurofilament heavy chain, to analyse the size and density of SMI-32-positive cortical pyramidal neurons in layer V of the PMC, the dorsolateral prefrontal cortex (DLPFC) and the supragenual anterior cingulate cortex (ACC) in 13 MND and eight control subjects. There was a statistically significant reduction in the density of SMI-32-immunoreactive (IR) pyramidal neurons within cortical layer V in the PMC, the DLPFC and the ACC in MND subjects compared with controls [t (19) = 2.91, P = 0.009; estimated reduction 25%; 95% CI = 8%, 40%]. In addition, we studied the density and size of interneurons immunoreactive for the calcium-binding proteins calbindin-D(28K) (CB), parvalbumin (PV) and calretinin (CR) in the same areas (PMC, DLPFC and ACC). Statistically significant differences in the densities of CB-IR neurons were observed within cortical layers V (P = 0.003) and VI (P = 0.001) in MND cases compared with controls. The densities of CR- and PV-IR neurons were not significantly different between MND and control cases, although there were trends towards reductions of CR-IR neuronal density within the same layers and of PV-IR neuronal density within cortical layer VI. Loss of pyramidal neurons and of GABAergic interneurons is more widespread than has been appreciated and is present in areas associated with neuroimaging and cognitive abnormalities in MND. These findings support the notion that MND should be considered a multisystem disorder.
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PMID:Cortical selective vulnerability in motor neuron disease: a morphometric study. 1513 Sep 49


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