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)

Neurofilaments are neuron-specific intermediate filaments. They are classed into three groups according to their molecular masses: neurofilament heavy, middle and light chains (NF-H, NF-M and NF-L). Neurofilaments assemble and form through the association of their central alpha-helical coiled-coil rod domains. NF-H and NF-M are distinct from NF-L as they contain a carboxyl-terminal tail domain, which appears to form connections with adjacent structures and other neurofilaments. Together with other axonal components such as microtubules, they form the dynamic axonal cytoskeleton. They maintain and regulate neuronal cytoskeletal plasticity through the regulation of neurite outgrowth, axonal caliber and axonal transport. Neurofilaments contain KSP repeats that are consensus motifs for the proline-directed kinases and are extensively phosphorylated in vivo, and their functions are thought to be regulated through their phosphorylation. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed kinase, whose activity is restricted to the neuron through the neuronal-specific distribution of its activators p35 and p39. Cdk5 is the only kinase that affects the electrophoretic mobility of human NF-H and is thought to be the major neurofilament kinase. Cdk5 is involved in crosstalk with other signal transduction pathways such as the mitogen-activated protein kinase and myelin-associated glycoprotein pathways to influence the phosphorylation of neurofilaments and other cytoskeletal proteins. Both the hyperactivation of Cdk5 activity and subsequent hyperphosphorylation of neurofilaments and the microtubule-associated protein tau have been implicated in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease and amyotrophic lateral sclerosis. Here we review the functions of neurofilaments and the significance of Cdk5 phosphorylation of neurofilaments.
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PMID:Cyclin-dependent kinase 5 in neurofilament function and regulation. 1467 12

We evaluated the expression of the type III intermediate filament (IF) protein, peripherin (PRP), in ubiquinated inclusions of motor neurons in amyotrophic lateral sclerosis (ALS). A previous study showed that overexpression of PRP in transgenic mice induces motor neuron disease with formation of PRP-containing inclusions before onset of symptoms [J. Cell Biol. 147 (3) (1999) 531]. To determine whether PRP inclusions occur in the human disease, we applied doublelabeling immunofluorescence to paraffin sections of the spinal cord obtained by autopsy of 40 ALS patients with sporadic disease and 39 controls. Inclusions that expressed immunoreactive ubiquitin and peripherin were recorded by video camera, and the sections were stained by hematoxylin and eosin (H&E) to define morphology. Lewy body-like inclusions (LBLIs) were seen in motor neuron perikarya of 9 of 40 ALS cases and none in controls; all LBLIs expressed peripherin. Skein-like inclusions (SLIs) were identified by ubiquitin, but did not express PRP with rare exceptions. Neither skein-like inclusions nor LBLIs expressed alpha B-crystallin, neurofilament protein (NF-L, NF-M and NF-H subunits), alpha-internexin, actin or alpha-synuclein. Immunoblot of the whole spinal cord exhibited a single 57-kDa band of peripherin in ALS patients and controls. Our data document the expression of peripherin in LBLIs, which may provide a clue to the pathogenesis of neurodegeneration in ALS.
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PMID:Expression of peripherin in ubiquinated inclusions of amyotrophic lateral sclerosis. 1467 9

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

Neurofilament middle and heavy chains (NFM and NFH) are heavily phosphorylated on their carboxy-terminal side-arm domains in axons. The mechanisms that regulate this phosphorylation are complex. Here, we demonstrate that p38alpha, a member of the stress-activated protein kinase family, will phosphorylate NFM and NFH on their side-arm domains. Aberrant accumulations of neurofilaments containing phosphorylated NFM and NFH side-arms are a pathological feature of amyotrophic lateral sclerosis (ALS) and we also demonstrate that p38alpha and active forms of p38 family kinases are associated with these accumulations. This is the case for sporadic and familial forms of ALS and also in a transgenic mouse model of ALS caused by expression of mutant superoxide dismutase-1 (SOD1). Thus, p38 kinases may contribute to the aberrant phosphorylation of NFM and NFH side-arms in ALS.
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PMID:p38alpha stress-activated protein kinase phosphorylates neurofilaments and is associated with neurofilament pathology in amyotrophic lateral sclerosis. 1520 59

Neuronal intermediate filaments consist of the NFL subunit linked with NFM and NFH, and their alterations have been proposed as a pathogenesic cause in motor neuron diseases. Depletion of the Nefl gene in mice mimicks the reduced NFL mRNA levels seen in amyotrophic lateral sclerosis and causes perikaryal accumulation of neurofilament proteins and axonal hypotrophy in motoneurons. NFL -/- mice were evaluated for regional brain metabolism by means of quantitative histochemical estimation of cytochrome oxidase (COx) activity. The NFL null mice displayed enzymatic activity alterations in numerous hindbrain regions, mainly the cerebellum, connected regions of the brainstem (red nucleus, vestibular nuclei, and reticular formation), and cranial nerve nuclei. All of the affected regions presented elevated COx activity, except for the Purkinje cells of the cerebellum and the magnocellular red nucleus, where enzymatic activity was lower. NFL-disrupted mice displayed functional alterations in brainstem sensorimotor regions affected in amyotrophic lateral sclerosis.
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PMID:Mice with the deleted neurofilament of low-molecular-weight (Nefl) gene: 1. Effects on regional brain metabolism. 1574 62

Amyotrophic lateral sclerosis (ALS), a neurodegenerative disease of unknown etiology, affects motor neurons leading to atrophy of skeletal muscles, paralysis and death. There is evidence for the accumulation of neurofilaments (NF) in motor neurons of the spinal cord in ALS cases. NF are major structural elements of the neuronal cytoskeleton. They play an important role in cell architecture and differentiation and in the determination and maintenance of fiber caliber. They are composed of three different polypeptides: light (NF-L), medium (NF-M) and heavy (NF-H) subunits. In the present study, we performed a morphological and quantitative immunohistochemical analysis to evaluate the accumulation of NF and the presence of each subunit in control and ALS cases. Spinal cords from patients without neurological disease and from ALS patients were obtained at autopsy. In all ALS cases there was a marked loss of motor neurons, besides atrophic neurons and preserved neurons with cytoplasmic inclusions, and extensive gliosis. In control cases, the immunoreaction in the cytoplasm of neurons was weak for phosphorylated NF-H, strong for NF-M and weak for NF-L. In ALS cases, anterior horn neurons showed intense immunoreactivity in focal regions of neuronal perikarya for all subunits, although the difference in the integrated optical density was statistically significant only for NF-H. Furthermore, we also observed dilated axons (spheroids), which were immunopositive for NF-H but negative for NF-M and NF-L. In conclusion, we present qualitative and quantitative evidence of NF-H subunit accumulation in neuronal perikarya and spheroids, which suggests a possible role of this subunit in the pathogenesis of ALS.
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PMID:Quantitative evidence for neurofilament heavy subunit aggregation in motor neurons of spinal cords of patients with amyotrophic lateral sclerosis. 1593 87

Peripherin is a type III neuronal intermediate filament detected in motor neuron inclusions of amyotrophic lateral sclerosis (ALS) patients. We previously reported that overexpression of peripherin provokes late-onset motor neuron dysfunction in transgenic mice. Here, we show that peripherin overexpression slows down axonal transport of neurofilament (NF) proteins, and that the transport defect precedes by several months the appearance of axonal spheroids in adult mice. Defective NF transport by peripherin up-regulation was further confirmed with dorsal root ganglia (DRG) neurons cultured from peripherin transgenic embryos. Immunofluorescence microscopy and western blotting revealed that excess peripherin provokes reduction in levels of hyperphosphorylated NF-H species in DRG neurites. Similarly the transport of a green fluorescent protein (GFP)-tagged NF-M, delivered by means of a lentiviral construct, was impaired in DRG neurites overexpressing peripherin. These results demonstrate that peripherin overexpression can cause defective transport of type IV NF proteins, a phenomenon that may account for the progressive formation of ALS-like spheroids in axons.
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PMID:Defective axonal transport of neurofilament proteins in neurons overexpressing peripherin. 1678 13

About 10 p. cent of amyotrophic lateral sclerosis (ALS) cases are familial. Most of the familial ALS (FALS) cases are clinically homogeneous. Among these families, autosomal dominant, X-linked or autosomal recessive transmission can be observed. Most of the causal mutations have been observed in the SOD1 gene. To date, more than one hundred different mutations have been described, but it remains unclear whether the mutation is always responsible for the phenotype. Penetrance of the mutation depends on age, with almost 90 p. 100 of penetrance at age 70 years. There is no anticipation. Worldwide, the most frequent mutation is A4V with dominant transmission, responsible for a severe, rapid form of the disease. The second most frequent mutation is D90A which is generally transmitted recessively, predominantly in the Scandinavian countries. The phenotype is characterized by a long lasting course (mean: 11 years). Other causal mutations have been described in the Alsine, Apex, NF-H and NAIP genes. Other genes can be considered as risk factors, like SMN2, APO E4, APEX, Dynactine, P-450 D6. Presymptomatic testing for FALS seems difficult because little information can be given to the patient regarding the responsibility of the mutation in the disease, age of onset, and disease trends. The same precautions as for Huntington's disease are needed. Genetic investigations can contribute to better understanding of the pathophysiology of ALS. Other causal genes in the 90 p. 100 of FALS without SOD1 mutation and eventually in the sporadic ALS cases may be disclosed. Genetic investigations also determine the precise role of a given SOD1 mutation because of the large number of potential SOD1 mutations, the variability of the transmission mode and the non-exceptional absence of proven causality for ALS.
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PMID:[Where is the role of the genetic investigations in amyotrophic lateral sclerosis?]. 1712 95

Under normal conditions, the proline-directed serine/threonine residues of neurofilament tail-domain repeats are exclusively phosphorylated in axons. In pathological conditions such as amyotrophic lateral sclerosis (ALS), motor neurons contain abnormal perikaryal accumulations of phosphorylated neurofilament proteins. The precise mechanisms for this compartment-specific phosphorylation of neurofilaments are not completely understood. Although localization of kinases and phosphatases is certainly implicated, another possibility involves Pin1 modulation of phosphorylation of the proline-directed serine/threonine residues. Pin1, a prolyl isomerase, selectively binds to phosphorylated proline-directed serine/threonine residues in target proteins and isomerizes cis isomers to more stable trans configurations. In this study we show that Pin1 associates with phosphorylated neurofilament-H (p-NF-H) in neurons and is colocalized in ALS-affected spinal cord neuronal inclusions. To mimic the pathology of neurodegeneration, we studied glutamate-stressed neurons that displayed increased p-NF-H in perikaryal accumulations that colocalized with Pin1 and led to cell death. Both effects were reduced upon inhibition of Pin1 activity by the use of an inhibitor juglone and down-regulating Pin1 levels through the use of Pin1 small interfering RNA. Thus, isomerization of lys-ser-pro repeat residues that are abundant in NF-H tail domains by Pin1 can regulate NF-H phosphorylation, which suggests that Pin1 inhibition may be an attractive therapeutic target to reduce pathological accumulations of p-NF-H.
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PMID:Inhibition of Pin1 reduces glutamate-induced perikaryal accumulation of phosphorylated neurofilament-H in neurons. 1762 62

Aberrant phosphorylation of neuronal cytoskeletal proteins is a key pathological event in neurodegenerative disorders such as Alzheimer disease (AD) and amyotrophic lateral sclerosis, but the underlying mechanisms are still unclear. Previous studies have shown that Pin1, a peptidylprolyl cis/trans-isomerase, may be actively involved in the regulation of Tau hyperphosphorylation in AD. Here, we show that Pin1 modulates oxidative stress-induced NF-H phosphorylation. In an in vitro kinase assay, the addition of Pin1 substantially increased phosphorylation of NF-H KSP repeats by proline-directed kinases, Erk1/2, Cdk5/p35, and JNK3 in a concentration-dependent manner. In vivo, dominant-negative (DN) Pin1 and Pin1 small interfering RNA inhibited epidermal growth factor-induced NF-H phosphorylation. Because oxidative stress plays an important role in the pathogenesis of neurodegenerative diseases, we studied the role of Pin1 in stressed cortical neurons and HEK293 cells. Both hydrogen peroxide (H(2)O(2)) and heat stresses induce phosphorylation of NF-H in transfected HEK293 cells and primary cortical cultures. Knockdown of Pin1 by transfected Pin1 short interference RNA and DN-Pin1 rescues the effect of stress-induced NF-H phosphorylation. The H(2)O(2) and heat shock induced perikaryal phospho-NF-H accumulations, and neuronal apoptosis was rescued by inhibition of Pin1 in cortical neurons. JNK3, a brain-specific JNK isoform, is activated under oxidative and heat stresses, and inhibition of Pin1 by Pin1 short interference RNA and DN-Pin1 inhibits this pathway. These results implicate Pin1 as a possible modulator of stress-induced NF-H phosphorylation as seen in neurodegenerative disorders like AD and amyotrophic lateral sclerosis. Thus, Pin1 may be a potential therapeutic target for these diseases.
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PMID:Pin1-dependent prolyl isomerization modulates the stress-induced phosphorylation of high molecular weight neurofilament protein. 1863 47


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