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)

We have previously shown that glial cell line-derived neurotrophic factor (GDNF), in addition to promoting the survival of dopaminergic neurons in cultures from embryonic rat ventral mesencephalon,also increases the activity of choline acetyltransferase (ChAT) in the cranial motoneurons present in these cultures (Zurn et al.: Neuroreport 6:113-118, 1994). By using the intermediate filament protein peripherin as a motoneuron marker, we report here that GDNF increases the number of motoneurons as well as the length of their neurites. Brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) also promote ChAT activity, motoneuron survival, and neurite outgrowth in these cultures, but to varying degrees. Although these three molecules have similar effects on cultured motoneurons, we provide evidence for a distinct mode of action of GDNF, BDNF, and CNTF, since combinations of GDNF and BDNF, GDNF and CNTF, and BDNF and CNTF have either additive or synergistic effects on ChAT activity and motoneuron number. In addition to the previously described motoneuron-specific neurotrophic factors BDNF and CNTF, GDNF combined with the latter two factors may provide an important tool for the treatment of human motoneuron diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy, both by increasing efficiency of treatment, and by decreasing the likelihood of deleterious side-effects.
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PMID:Combined effects of GDNF, BDNF, and CNTF on motoneuron differentiation in vitro. 872 21

Peripherin, a neuronal intermediate filament protein associated with axonal spheroids in amyotrophic lateral sclerosis (ALS), induces the selective degeneration of motor neurons when overexpressed in transgenic mice. To further clarify the selectivity and mechanism of peripherin-induced neuronal death, we analyzed the effects of peripherin overexpression in primary neuronal cultures. Peripherin overexpression led to the formation of cytoplasmic protein aggregates and caused the death not only of motor neurons, but also of dorsal root ganglion (DRG) neurons that were cultured from dissociated spinal cords of peripherin transgenic embryos. Apoptosis of DRG neurons containing peripherin aggregates was dependent on the proinflammatory central nervous system environment of spinal cultures, rich in activated microglia, and required TNF-alpha. This synergistic proapoptotic effect may contribute to neuronal selectivity in ALS.
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PMID:Apoptotic death of neurons exhibiting peripherin aggregates is mediated by the proinflammatory cytokine tumor necrosis factor-alpha. 1160 19

Peripherin is a neuronal intermediate filament protein that is expressed chiefly in motor neurons and other nerve cells that project into the peripheral nervous system. Transgenic mice that over-express peripherin develop motor neuron degeneration, suggesting that mutations in peripherin could contribute to the development of motor neuron disease. In this paper, we report the identification of a homozygous mutation in the peripherin gene (PRPH) in a patient with amyotrophic lateral sclerosis (ALS). The mutation resulted in a substitution of aspartate with tyrosine at amino acid position 141, which is located within the first linker region of the rod domain. Immunocytochemical analysis of the spinal cord of the patient upon autopsy revealed distinctive large aggregates within the cell bodies of residual spinal motor neurons that contained peripherin and was also immunoreactive with antibodies to the neurofilament proteins. In order to study the effect of the mutation on peripherin assembly, we performed transient transfections. Unlike wild-type peripherin, which self-assembles to form a filamentous network, the mutant peripherin was prone to form aggregates in transfected cells, indicating that the mutation adversely affects peripherin assembly. Moreover, the neurofilament light (NF-L) protein was not able to rescue the mutant protein from forming aggregates. These data imply that mutation of PRPH is a contributing factor for ALS.
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PMID:A pathogenic peripherin gene mutation in a patient with amyotrophic lateral sclerosis. 1544 84

The mechanism by which mutated copper-zinc superoxide dismutase (SOD1) causes familial amyotrophic lateral sclerosis is believed to involve an adverse gain of function, independent of the physiological antioxidant enzymatic properties of SOD1. In this study, we have observed that mutant SOD1 (G41S, G85A, and G93A) but not the wild type significantly reduced the stability of the low molecular weight neurofilament mRNA in a dosage-dependent manner. We have also demonstrated that mutant SOD1 but not the wild type bound directly to the neurofilament mRNA 3'-untranslated region and that the binding was necessary to induce mRNA destabilization. These observations provide an explanation for a novel gain of function in which mutant SOD1 expression in motor neurons alters an intermediate filament protein expression.
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PMID:Mutant copper-zinc superoxide dismutase binds to and destabilizes human low molecular weight neurofilament mRNA. 1550 37

There is growing evidence for the involvement of cytoskeletal defects in the pathogenesis of motor neuron disease and especially in components of the microtubule-based transport system. Here we will review our recent work aiming to elucidate the role of peripherin in amyotrophic lateral sclerosis (ALS) and to address the mechanism of disease caused by deletions in the ALS2 gene that cause recessive forms of juvenile ALS and primary lateral sclerosis (PLS). Peripherin is an intermediate filament protein detected in spheroids, a hallmark of ALS, and increased levels of peripherin mRNA have been found in some ALS cases. Our transgenic mouse and cell culture studies support the view of a peripherin involvement in ALS. However, a gene knockout approach demonstrated that peripherin is not a key contributor of motor neuron disease caused by mutant superoxide dismutase linked to familial ALS. A recent breakthrough in the field of ALS came with the discovery of frameshift deletions in the ALS2 gene coding for Alsin. Our transfection experiments in cultured cells suggest that Alsin is a cytoskeletal protein with dual endosomal and centrosomal localizations. We have generated a mouse knockout for Alsin that develops progressive motor dysfunction during ageing. Thus, it is anticipated that this mouse model will be useful to investigate the pathogenic pathways linked to Alsin gene mutations.
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PMID:Cytoskeletal defects in amyotrophic lateral sclerosis (motor neuron disease). 1577 54

Peripherin is a 57 kDa Type III intermediate filament protein associated with neurite extension, neuropathies such as amyotrophic lateral sclerosis, and cranial nerve and dorsal root projections. However, knowledge of peripherin expression in the CNS is limited. We have used immunoperoxidase histochemistry to characterise peripherin expression in the mouse hindbrain, including the inferior colliculus, pons, medulla and cerebellum. Peripherin immunolabelling was observed in the nerve fibres and nuclei that are associated with all cranial nerves [(CN) V-XII] in the hindbrain. Peripherin expression was prominent in the cell bodies and axons of the mesenchephalic trigeminal nucleus and the pars compacta region of nucleus ambiguus, and in the fibres that comprise the solitary tract, the descending spinal trigeminal tract and the trigeminal and facial nerves. A small proportion of peripherin positive fibres in CN VIII likely arise from cochlear type II spiral ganglion neurons. Peripherin positive fibres were also observed in the inferior cerebellar peduncle and folia in the intermediate zone of the cerebellum. Antibody specificity was confirmed by absence of labelling in hindbrain tissue from peripherin knockout mice. This study shows that in the adult mouse hindbrain, peripherin is expressed in discrete neuronal subpopulations that have sensory, motor and autonomic functions.
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PMID:Neuronal expression of peripherin, a type III intermediate filament protein, in the mouse hindbrain. 1789 57

Peripherin is a type III neuronal intermediate filament protein detected within the intraneuronal inclusions characteristic of amyotrophic lateral sclerosis. The constitutively expressed peripherin isoform is encoded by all nine exons of the human and mouse peripherin genes to generate a protein species of approximately 58 kDa on sodium dodecyl sulfate-polyacrylamide gels. Expression of this isoform, termed Per-58, generates a filament network in transfected SW13 vim cells. On immunoblots of cell lysates derived from these transfected cells, we have consistently observed a second peripherin species of approximately 45 kDa. In this study, we show that this species is a novel peripherin isoform generated through the use of an in-frame downstream initiation codon. This isoform, that we have designated Per-45, is co-expressed together with Per-58 and, thus, constitutive in both human and mouse. Using mutational analysis, we show that Per-45 is required for normal network formation, with the absence of Per-45 leading to irregular filamentous structures. We further show that peripherin expression in the normal nervous system is characterized by tissue-specific Per-58 : Per-45 isoform ratios. Taken together, these results identify novel processing requirements for peripherin expression and indicate a hitherto unrecognized role for neuronal intermediate filament network formation through intra-isoform associations.
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PMID:A novel peripherin isoform generated by alternative translation is required for normal filament network formation. 1820 47

The neuronal intermediate filament protein peripherin is a component of ubiquitinated inclusions and of axonal spheroids in amyotrophic lateral sclerosis (ALS). Overexpression of peripherin causes motor neuron degeneration in transgenic mice and variations within the peripherin gene have been identified in ALS cases. We have shown previously the abnormal expression of a neurotoxic peripherin splice variant in transgenic mice expressing mutant superoxide dismutase-1. These findings indicated that abnormalities of peripherin splicing may occur in ALS. In the current study, peripherin splice variants were identified by reverse transcription-PCR of human neuronal RNA and comparisons in expression made between control and ALS spinal cord using Western blot analysis and immunocytochemistry. Using this approach we have identified a novel peripherin transcript retaining introns 3 and 4 that results in a 28 kDa splice isoform, designated Per 28. Using an antibody specific to Per 28, we show that this isoform is expressed at low stoichiometric levels from the peripherin gene, however causes peripherin aggregation when its expression is upregulated. Importantly we show an upregulation of Per 28 expression in ALS compared with controls, at both the mRNA and protein levels, and that Per 28 is associated with disease pathology, specifically round inclusions. These findings are the first to establish that peripherin splicing abnormalities occur in ALS, generating aggregation-prone splice isoforms.
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PMID:An aggregate-inducing peripherin isoform generated through intron retention is upregulated in amyotrophic lateral sclerosis and associated with disease pathology. 1828

A hallmark of the afflicted nervous tissue in amyotrophic lateral sclerosis is the presence of protein aggregates, which to a large extent contain the intermediate filament protein peripherin. Here we show that activation of protein kinase C (PKC) or overexpression of PKCepsilon induces the aggregation of peripherin in cultured neuroblastoma cells with elevated amounts of peripherin. The formation of aggregates was coupled to an increased apoptosis, suggesting a functional link between these events. Both induction of aggregates and apoptosis were suppressed in cells that had been transfected with small interfering RNAs targeting PKCepsilon. PKCepsilon and peripherin associate as shown by co-immunoprecipitation, and the interaction is dependent on and mediated by the C1b domain of PKCepsilon. The interaction was specific for PKCepsilon since corresponding structures from other isoforms did not co-precipitate peripherin, with the exception for PKCeta and -, which pulled down minute amounts. PKCepsilon interacts with vimentin through the same structures but does not induce its aggregation. When the PKCepsilon C1b domain is expressed in neuroblastoma cells together with peripherin, both phorbol ester-induced peripherin aggregation and apoptosis are abolished, supporting a model in which PKCepsilon through its interaction with peripherin facilitates its aggregation and subsequent cell death. These events may be prevented by expressing molecules that bind peripherin at the same site as PKCepsilon.
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PMID:Protein kinase Cepsilon binds peripherin and induces its aggregation, which is accompanied by apoptosis of neuroblastoma cells. 1840 15

Glial fibrillary acidic protein (GFAP) is an intermediate filament protein that is highly expressed in reactive astrocytes. Increased production of GFAP is a hallmark of astrogliosis in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). However, the physiological and pathological roles of GFAP, particularly in chronic neurodegenerative conditions, remain unclear. To address this issue, we here investigate whether absence of GFAP affects the phenotypic expression of motor neuron disease (MND) using an H46R mutant Cu/Zn superoxide dismutase-expressing mouse model of ALS (SOD1(H46R)). GFAP deficient SOD1(H46R) mice showed a significant shorter lifespan than SOD1(H46R) littermates. Further, at the end stage of disease, loss of GFAP resulted in increased levels of Vim and Aif1 mRNAs, encoding vimentin and allograft inflammatory factor 1 (AIF1), respectively, in the spinal cord, although no discernible differences in the levels and distribution of these proteins between SOD1(H46R) and GFAP-deficient SOD1(H46R) mice were observed. These results suggest that loss of GFAP in SOD1(H46R) mice marginally accelerates the disease progression by moderately enhancing glial cell activation. Our findings in a mouse model of ALS may have implication that GFAP is not necessary for the initiation of disease, but it rather plays some modulatory roles in the progression of ALS/MND.
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PMID:Loss of glial fibrillary acidic protein marginally accelerates disease progression in a SOD1(H46R) transgenic mouse model of ALS. 2145 31


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