Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Familial amyloidosis, British type, is an autosomal dominant disease characterized by progressive dementia, spastic paralysis and ataxia. The identity of the accumulating amyloid is not known, thus preventing the definitive classification of the disease. Biochemical methods were used to characterize the nature of the amyloid deposits from the brain tissue of one individual who died with this disease. The purified tissue material was subjected to trypsin digestion and subsequent N-terminal sequence analysis. Major tryptic fragments yielded the sequences VGINYQPPTVVPGGDLAK, FDLMYAK, GLTVPEL and GYLTVAAVFR, which are all tryptic fragments of the C-termini of human tubulin subunits alpha and beta. Synthetic peptides based on the sequences of these fragments formed amyloid fibrils in vitro fitting the characteristic definition of amyloid. These findings suggest that the C-terminal fragments of both alpha- and beta-tubulin are closely associated to the amyloid deposits of familial amyloidosis, British type.
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PMID:C-terminal fragments of alpha- and beta-tubulin form amyloid fibrils in vitro and associate with amyloid deposits of familial cerebral amyloid angiopathy, British type. 861 14

Miller-Fisher syndrome is an autoimmune neuropathy characterized by ataxia, areflexia and ophthalmoplegia, and in the majority of cases the presence of high titres of anti-GQ1b ganglioside antibodies. In an ex vivo model, human and mouse anti-GQ1b antibodies have been shown previously to induce a complement-dependent alpha-latrotoxin-like effect on the murine motor endplate, i.e. they bring about massive quantal release of acetylcholine and eventually block neuromuscular transmission. Using immunofluorescence microscopy with image analysis, we show here that the late stages of this electrophysiological effect temporally coincide with the loss of heavy neurofilament (200 kDa) and type III beta-tubulin immunostaining and structural breakdown of the nerve terminal, as demonstrated by electron microscopy. Ultrastructurally, axon terminals were disorganized, depleted of vesicles, and subdivided by the infiltrating processes of capping Schwann cells. These findings provide clear pathological evidence to support a role for anti-ganglioside antibodies in mediating nerve terminal injury and further advance the view that this site may be of importance as a target in some human neuropathies.
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PMID:Anti-GQ1b ganglioside antibodies mediate complement-dependent destruction of the motor nerve terminal. 1133 92

Tri-ortho-cresyl phosphate (TOCP) is an organophosphorus ester. It is capable of producing organophosphorus ester induced delayed neurotoxicity (OPIDN) in human being and sensitive animals, which is characterized by ataxia that progresses to paralysis after 1-3 weeks following exposure to some organophosphorus ester. In present study, 18 adult hens were divided randomly into three groups, i.e. two experimental groups and control group (n = 6 each group). All hens were 10 months old and weighted 1.5-2.0 kg. The hens in two experimental groups were treated with TOCP by gavage at single dosages of 375 and 750 mg/kg respectively. TOCP was dissolved in corn oil and administered at 0.65 ml/kg. Six control hens received an equivalent volume of corn oil by gavage. All hens were sacrificed after 21 days of treatment and the sciatic nerves were dissected, homogenized and used for the determination of cytoskeletal proteins by western blotting. The levels of neurofilament (NF) subunits were decreased both in supernatant and pellet of sciatic nerves, and the most noticeable decrease in levels of NF subunits protein was observed in neurofilament medium (NF-M). Compared to the control hens, neurofilament heavy (NF-H) level decreased by 36 and 38% (P < 0.01) in the pellet and by 27 and 26% (P < 0.05) in the supernatant of sciatic nerves of hens treated with 375 and 750 mg/kg TOCP respectively. The reduction of NF-M were 36 and 68% (P < 0.01) in pellet, 50 and 67% (P < 0.01) in supernatant at 375 and 750 mg/kg dosage respectively. The neurofilament light (NF-L) lessened slightly, but the relative percentage of integrated optical density (IOD) was no significant alteration when compared to the control hens. There were significant decreases in levels of alpha-tubulin, beta-tubulin in pellet and alpha-tubulin, beta-tubulin, beta-actin in supernatant of sciatic nerves in TOCP-treated hens. Thus, the decreases of cytoskeletal proteins suggested the possible involvement of them in delayed neurotoxicity.
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PMID:Tri-ortho-cresyl phosphate (TOCP) decreases the levels of cytoskeletal proteins in hen sciatic nerve. 1530 95

Organophosphorus ester-induced delayed neurotoxicity (OPIDN) is a neurodegenerative disorder characterized by ataxia progressing to paralysis with a concomitant central and peripheral distal axonapathy. Diisopropylphosphorofluoridate (DFP) produces OPIDN in the chicken, which results in mild ataxia in 7-14 days and severe paralysis as the disease progresses with a single dose. White leghorn layer hens were treated with DFP (1.7 mg/kg, sc) after prophylactic treatment with atropine (1 mg/kg, sc) in normal saline and eserine (1 mg/kg, sc) in dimethyl sulfoxide. Control groups were treated with vehicle propylene glycol (0.1 mL/kg, sc), atropine in normal saline and eserine in dimethyl sulfoxide. The hens were sacrificed at different time points such as 2, 4, and 8 h, as well as 1, 2, 5, 10 and 20 days, and the tissues from cerebrum, midbrain, cerebellum brainstem and spinal cord were quickly dissected and frozen for protein (western) and mRNA (northern) studies. Subcellular fractionation, SDS-PAGE and immunoblotting of the nuclear and supernatant fractions using standard protocols from spinal cord and cerebrum showed differential expression of protein levels of PKA, CREB and phosphorylated CREB (p-CREB). There was an increase in PKA level in spinal cord nuclear fraction after 4 h (130+/-5%) and 8 h (133+/-6 %), while cerebrum nuclear fraction showed decrease (77+/-5%) at 4 h and remained at the same level at 8 h. No change was seen in either spinal cord or cerebrum soluble fraction at any time points. There was an increase in CREB level in the spinal cord supernatant (133+/-3%) after 5 days, while nuclear and supernatant fraction of the cerebrum did not show any alterations at any time point. p-CREB was induced in the spinal cord nuclear fraction at 1 day (150+/-3%) and 5 days (173+/-7%) of treatment, in contrast to the decreased levels p-CREB (72+/-4%) at 10 days in cerebrum nuclear fraction. Supernatant fraction of spinal cord and cerebrum did not show any changes in pCREB at time points studied. Similarly another set of animals were treated with DFP and perfused using standard protocols and immunohistochemistry for p-CREB in the brain and spinal cord confirmed the overall protein expression pattern identified by western analysis. Expression of beta-tubulin subtypes (1, 2, 3, and 4), studied by Northern blotting showed complex and differential pattern, while immunohistochemistry of the anti-beta-tubulin for the entire period of OPIDN developmental stages showed early induction and persistence even in the disintegrating axonal and non-neuronal structures of the CNS. These data thus strongly suggest that early cytoskeletal damage at molecular level mediated by PKA/p-CREB pathways leads to the culmination of gross (microscopically observable) level cytoskeletal changes in various components of central nervous system (CNS), consistent with our earlier findings. Thus, the differential protein expression of PKA, CREB, p-CREB and beta-tubulin subtypes appear to contribute to the initiation, progression and development of OPIDN, probably by recruiting other molecular pathways specific to various components of nervous system.
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PMID:DFP initiated early alterations of PKA/p-CREB pathway and differential persistence of beta-tubulin subtypes in the CNS of hens contributes to OPIDN. 1966 48

Ataxin-3 consists of an N-terminal globular Josephin domain and an unstructured C-terminal region containing a stretch of consecutive glutamines that triggers an inherited neurodegenerative disorder, spinocerebellar ataxia type 3, when its length exceeds a critical threshold. The pathology results from protein misfolding and intracellular accumulation of fibrillar amyloid-like aggregates. Plenty of work has been carried out to elucidate the protein's physiological role(s), which has shown that ataxin-3 is multifunctional; it acts as a transcriptional repressor, and also has polyubiquitin-binding/ubiquitin-hydrolase activity. In addition, a recent report shows that it participates in sorting misfolded protein to aggresomes, close to the microtubule-organizing center. Since a thorough understanding of the protein's physiological role(s) requires the identification of all the molecular partners interacting with ataxin-3, we pursued this goal by taking advantage of two-dimensional chromatography coupled to tandem mass spectrometry. We found that different ataxin-3 constructs, including the sole Josephin domain, bound alpha- and beta-tubulin from soluble rat brain extracts. Coimmunoprecipitation experiments confirmed this interaction. Also, normal ataxin-3 overexpressed in COS7 cultured cells partially colocalized with microtubules, whereas an expanded variant only occasionally did so, probably due to aggregation. Furthermore, by surface plasmon resonance we determined a dissociation constant of 50-70nM between ataxin-3 and tubulin dimer, which strongly supports the hypothesis of a direct interaction of this protein with microtubules in vivo. These findings suggest an involvement of ataxin-3 in directing aggregated protein to aggresomes, and shed light on the mode of interaction among the different molecular partners participating in the process.
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PMID:Proteomic and biochemical analyses unveil tight interaction of ataxin-3 with tubulin. 1966 35