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)

Because transgenic mice expressing an altered stoichiometry of neurofilament proteins develop a motor neuron degeneration associated with neurofilamentous aggregate formation similar to that found in amyotrophic lateral sclerosis (ALS), we studied the expression of intermediate filament proteins in sporadic ALS. Archival cervical spinal cord paraffin-embedded sections from 11 disease and 11 control cases were studied by either in situ hybridization using 35S-labeled riboprobes or immunohistochemically using specific antibodies for the individual neurofilament subunit proteins, alpha-internexin, nestin, peripherin, vimentin, beta-actin, or Talpha1-tubulin. Median NFL, alpha-internexin, and peripherin steady-state mRNA levels were significantly reduced in the lateral motor neuron cell column (p < 0.05) of ALS cases, while neither NFM nor NFH mRNA levels were altered. ALS cases demonstrated an elevation of beta-actin mRNA levels (p < 0.01) with no increase in Talpha1-tubulin mRNA levels. No motor neuronal expression of nestin or vimentin was observed. Ubiquitin-immunoreactive perikaryal aggregates were immunoreactive for NFH or beta-actin, but not for peripherin, alpha-internexin, vimentin, or nestin. In contrast, neuroaxonal spheroids were strongly immunoreactive for NFH and peripherin, but not for beta-actin, alpha-internexin, vimentin, or nestin. These findings suggest that the stoichiometry of cytoskeletal protein expression in ALS spinal motor neurons is significantly altered in a pattern conducive to the formation of neurofilamentous aggregates.
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PMID:Characterization of neuronal intermediate filament protein expression in cervical spinal motor neurons in sporadic amyotrophic lateral sclerosis (ALS). 1108 75

Nestin is one of the intermediate filament proteins and mainly expressed during the development of the central nervous system. We examined the cerebellum of patients with Creutzfeldt-Jakob disease (CJD), multiple system atrophy and amyotrophic lateral sclerosis, using anti-human nestin antibodies. The antibodies strongly immunostained the cytoplasm, dendrites and torpedoes of Purkinje cells in CJD. However, Purkinje cells in other neurodegenerative disorders were not nestin-immunoreactive. Nestin immunoreactivities became more marked as the pathological severity in the cerebellum increased. Our findings suggest that nestin is strongly expressed in Purkinje cells in pathologically advanced CJD and show the possibility that Purkinje cells are being reactivated to promote survival.
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PMID:Expression of nestin in Purkinje cells in patients with Creutzfeldt-Jakob disease. 1462 35

We have examined the steady-state levels of intermediate filament mRNA in amyotrophic lateral sclerosis using the RNAse protection assay (NFL, NFM, NFH; corrected against GAPDH) or by PCR (peripherin, alpha-internexin, nestin, and vimentin; corrected against beta-actin). Significant elevations of NFL and peripherin mRNA levels were observed within the ALS cervical and lumbar spinal cord, with all other IF mRNA levels being comparable between control and ALS cases. These findings suggest that disturbances in both NFL and peripherin expression, independently known to contribute to the generation of motor neuron dysfunction in transgenic mice, are evident in ALS.
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PMID:Intermediate filament steady-state mRNA levels in amyotrophic lateral sclerosis. 1502 Feb 20

The organization, distribution, and function of neural progenitor cells (NPCs) in the adult spinal cord during motor neuron degeneration in amyotrophic lateral sclerosis (ALS) remain largely unknown. Using nestin promoter-controlled LacZ reporter transgenic mice and mutant G93A-SOD1 transgenic mice mimicking ALS, we showed that there was an increase of NPC proliferation, migration, and neurogenesis in the lumbar region of adult spinal cord in response to motor neuron degeneration. The proliferation of NPCs detected by bromodeoxyurindine incorporation and LacZ staining was restricted to the ependymal zone surrounding the central canal (EZ). Once the NPCs moved out from the EZ, they lost the proliferative capability but maintained migratory function vigorously. During ALS-like disease onset and progression, NPCs in the EZ migrated initially toward the dorsal horn direction and then to the ventral horn regions, where motor neurons have degenerated. More significantly, there was an increased de novo neurogenesis from NPCs during ALS-like disease onset and progression. The enhanced proliferation, migration, and neurogenesis of (from) NPCs in the adult spinal cord of ALS-like mice may play an important role in attempting to repair the degenerated motor neurons and restore the dysfunctional circuitry which resulted from the pathogenesis of mutant SOD1 in ALS.
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PMID:Motor neuron degeneration promotes neural progenitor cell proliferation, migration, and neurogenesis in the spinal cords of amyotrophic lateral sclerosis mice. 1609 95

Transgenic rats expressing a mutated form of the human Cu/Zn superoxide dismutase (hSOD1(G93A)) develop an amyotrophic lateral sclerosis (ALS)-like phenotype, including motor neurone degeneration and reactive gliosis in the spinal cord. This study aimed at examining the presence of endogenous neural progenitors in the lumbar spinal cord of these rats at the end-stage of the disease. Immunohistochemical data clearly demonstrated the induced expression of the stem cell factor reported as a chemoattractant and survival factor for neural stem cells as well as nestin (neuro-epithelial stem cell intermediate filament) in the spinal cord sections. While the stem cell factor immunolabelling appeared diffuse throughout the gray matter, nestin labelling was restricted to clusters within the ventral horn. Interestingly, as paralysis regularly develops asymmetrically, induction of nestin was only detected on the ipsilateral side of the predominant symptoms. Finally, immunohistochemical detection of the stem cell factor receptor (c-Kit) revealed its specific induction which coincided with nestin immunolabelling. Together, these results are indicative of endogenous recruitment of neural progenitors within lesioned tissues and could support the development of treatments involving endogenous or exogenous stem cells.
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PMID:Unilateral induction of progenitors in the spinal cord of hSOD1(G93A) transgenic rats correlates with an asymmetrical hind limb paralysis. 1654 Feb 43

Amyotrophic lateral sclerosis (ALS) is a fatal adult human disease caused by motor neuron degeneration. Stem cell therapy might be a treatment for ALS. The adult mammalian forebrain has neural stem cells (NSCs) and neural progenitor cells (NPCs) in the anterior subventricular zone (SVZa), rostral migratory stream (RMS), olfactory bulb (OB) core, and dentate gyrus (DG). These cells could be used to rescue or replace degenerating upper and lower motor neurons through endogenous recruitment or autologous/allogenic transplantation. We evaluated the competency of forebrain NSCs and NPCs in transgenic (tg) mice harboring human mutant superoxide dismutase-1 (mSOD1), a model of ALS. Tg human wild-type SOD1 (wtSOD1) mice and non-tg mice were controls. Bromodeoxyuridine (BrdU) labeling of cells, a marker for cell proliferation and other events, was reduced in a niche-specific pattern in presymptomatic and symptomatic mice, with the SVZa having greater reductions than the RMS, OB, and DG. Different NSC and NPC complements were evaluated by localizing nestin, neural cell adhesion molecule, distalless-2 transcription factor, vimentin, and glial fibrillary acidic protein. In symptomatic mice, NSC markers were reduced, whereas NPC markers were unchanged or elevated. Neurogenesis was preserved in symptomatic mSOD1 mice. NSC/NPC competence assessment in vitro revealed that mSOD1 SVZa cells had the ability to proliferate and form neurospheres but had an impaired response to mitogen stimulation. We conclude that adult mSOD1 ALS mice have abnormalities in forebrain NSCs, but the essential features of NSC/NPCs remained in presymptomatic and symptomatic mice.
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PMID:The adult neural stem and progenitor cell niche is altered in amyotrophic lateral sclerosis mouse brain. 1673 75

We investigated three steps of neural precursor cell activation--proliferation, migration, and differentiation--in amyotrophic lateral sclerosis spinal cord treated with intrathecal infusion of epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF2) into the lumbar spinal cord region of normal and symptomatic transgenic (Tg) mice with a mutant human Cu/Zn superoxide dismutase (SOD1) gene. We observed that 5-bromodeoxyuridine (BrdU) + nestin double-labeled neural precursor cells increased in the spinal cords of Tg mice compared with non-Tg mice, with a much greater increase produced by EGF and FGF2 treatment. The number of BrdU + nestin double-labeled cells was larger than that of BrdU + ionized calcium-binding adapter molecule-1 (Iba1), BrdU + glial fibrillary acidic protein (GFAP), or BrdU + highly polysialylated neural cell adhesion molecule (PSA-NCAM) double-labeled cells, but none expressed neuronal nuclear antigen (NeuN). On further analysis of the gray matter of Tg mice, the number of BrdU + nestin and BrdU + PSA-NCAM double-labeled cells increased more in the ventral horns than the dorsal horns, which was again greatly enhanced by EGF and FGF2 treatment. Because neural precursor cells reside close to the ependyma of central canal, the present study suggests that proliferation and migration of neural precursor cells to the ventral horns is greatly activated in symptomatic Tg mice and is further enhanced by EGF and FGF2 treatment and, furthermore, that the neural precursor cells preferentially differentiate into neuronal precursor cells instead of astrocytes in Tg mice with EGF and FGF2 treatment.
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PMID:Intrathecal injection of epidermal growth factor and fibroblast growth factor 2 promotes proliferation of neural precursor cells in the spinal cords of mice with mutant human SOD1 gene. 1690 95

The superoxide dismutase 1(G93A G1H) (SOD1(G93A G1H)) transgenic mouse is a model of familial human amyotrophic lateral sclerosis (ALS) that has progressive neurodegeneration within the spinal cord and brainstem. In this study, we investigated the number and differentiation of neural precursor cells (NPCs). Nestin-positive NPCs were rarely seen in the nervous system of wild type controls or pre-disease mice at post-natal days 30 and 60. With disease onset on post-natal day 90, nestin labeled NPCs proliferated preferentially in the brainstem with maximal number and density at post-natal day 120. NPCs did not double-label with CNPase or O(4) markers of oligodendrocytes. The majority of the NPCs co-labeled with the astrocyte maker glial fibrillary acidic protein (GFAP) and a small number with the neuronal marker NeuN. At disease onset, 73 and 10% of NPCs co-expressed GFAP and NeuN respectively while at severe disease stage, 80 and 8% of the NPCs co-expressed GFAP and NeuN. Proliferating cell nuclear antigen (PCNA) was used to confirm that at least some of these cells undergo mitosis. Future studies could be directed at controlling the differentiation of these endogenous NPCs into neurons and astrocytes in order to ameliorate the degeneration within the brainstem of the ALS mouse.
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PMID:Increased number and differentiation of neural precursor cells in the brainstem of superoxide dismutase 1(G93A) (G1H) transgenic mouse model of amyotrophic lateral sclerosis. 1743 5

In mammalian spinal cords, no neurogenesis has been observed after initial development. However developed mammalian spinal cords seemingly contain neural stem cells (NSC), which can give rise to neurons and glial cells when they are placed in appropriate environments. The purpose of the present paper was to investigate the developing, developed, and diseased human spinal cord to see which cell types have an immunophenotype similar to NSC. In 12 specimens from preterm neonates and term infants up to 14 months old, nestin was expressed in cells that extended fibrous processes and were located around the midline in the ependymal layer. In all the preterm neonates, Musashi-1 and glial fibrillary acidic protein (GFAP) were also expressed in this subpopulation, whereas Lewis X was detected in a less restricted subpopulation. Nestin expression by these cells was not detected in most adult spinal cords, but was observed in three spinal cords from 13 amyotrophic lateral sclerosis patients and eight of 14 spinal cords involved by the tumor. The present observations suggest that during gestation a subpopulation of cells in the ependymal layer remains undifferentiated as potential NSC/neural progenitor cells, and becomes unidentifiable in early infancy. These cells, however, appear in response to disease conditions, especially tumor involvement.
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PMID:Distribution of nestin and other stem cell-related molecules in developing and diseased human spinal cord. 1753 67

Regenerative medicine through neural stem cells (NSCs) or neural progenitor cells (NPCs) has been proposed as an alterative avenue for restoring neurological dysfunction in amyotrophic lateral sclerosis (ALS). It is critical to understand the organization and distribution of endogenous adult NPCs in response to motor neuron degeneration before regenerative medicine can be applied for ALS therapy. For this reason, we analyzed the temporal response of NPCs to motor neuron degeneration in the spinal cord and brain using nestin enhancer-driven LacZ reporter transgenic mice (pNes-Tg mice, control) and bi-transgenic mice containing both the nestin enhancer-driven LacZ reporter gene and mutant G93A-SOD1 gene (Bi-Tg mice). We observed an increase of NPCs in the dorsal horns of the spinal cord at the disease onset and progression stages in the Bi-Tg mice compared with that of age-matched pNes-Tg control mice. In contrast, an increase of NPCs in the ventral horns was detected at the disease progression stage. On the other hand, an increase of NPCs in the motor cortex at the disease-onset stage, but not at the disease progression stage, was detected. Furthermore, a decrease of NPCs in the lateral ventricle at the disease progression stage was observed, whereas no difference in the number of NPCs in the hippocampus was detected at the disease onset and progression stages. Some of the NPCs differentiate into neuron-like cells in response to motor neuron degeneration. The organization and distribution of endogenous adult NPCs in the ALS-like transgenic mice at the disease onset and progression stages provide fundamental bases for consideration of regenerative therapy of ALS by increasing de novo neurogenesis.
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PMID:Temporal response of neural progenitor cells to disease onset and progression in amyotrophic lateral sclerosis-like transgenic mice. 1778 31


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