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)

Using quantitative immunoblotting, we have measured the level of two mammalian neurofilament proteins, the 68-kDa NF-L and the 66-kDa NF-66 (alpha-internexin), in the rat CNS during development. NF-66 is localized in neurons and neuronal processes in both embryonic and postnatal brain. Importantly, NF-66 is more abundant than NF-L in both forebrain and cerebellum during development. The prevalence of NF-66 over NF-L is most pronounced in brain gray matter. The expression of both NF-66 and NF-L increases continuously during the first month after birth. In situ hybridization demonstrated that NF-66, but not NF-L is, expressed in the cerebellar granule cells. Our findings suggest that the neurofilaments are heterogeneous in developmental expression, among neuronal subtypes and in composition. Human NF-66 neurofilament has recently been mapped to chromosome 10q24. Careful analysis of the human genome map indicates NF-66 gene lies within the critical region of infantile-onset spinocerebellar ataxia (IOSCA). The characteristic developmental expression and spatial localization of the NF-66 gene suggests it as a candidate gene for the disease.
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PMID:Heterogeneous expression of neurofilament proteins in forebrain and cerebellum during development: clinical implications for spinocerebellar ataxia. 943 34

Diisopropyl phosphorofluoridate (DFP) is an organophosphorus ester, and a single injection of this compound (1.7 mg/kg, s.c.) produces delayed neurotoxicity (OPIDN) in hens in 7-14 days. Clinically, the disease is marked by hindlimb ataxia followed by paralysis after some time. A characteristic feature of this neuropathy is axonal swelling in the initial stages and comparative dissolution of the accumulated material and degeneration of distal axons with disease progression. Axonal swelling consists of aggregated neurofilaments, microtubules, and proliferated smooth endoplasmic reticulum. We studied expression of neurofilament (NF) mRNAs in brain regions and spinal cord to elucidate their role in OPIDN. There was a 50-200% increase in NF transcripts in 24 hr after DFP administration. The NF-L mRNA level started falling after 1-5 days and came down to control level in susceptible brain regions (i.e. cerebellum and brainstem) and spinal cord, but not in cerebral cortex, which does not show degeneration of axons in OPIDN. Cerebral cortex exhibited elevated levels of both NF-L and NF-M transcripts in DFP-treated hens throughout the period of observation. The induction of NF messages is consistent with the previously reported effect on extension of neurites of human neuroblastoma cells in culture. The transient increase in NF messages in susceptible tissues either may be responsible for the delayed degeneration of axons in OPIDN or is the result of interruption of regulatory signal due to progressive degeneration of axons.
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PMID:Enhanced mRNA expression of neurofilament subunits in the brain and spinal cord of diisopropyl phosphorofluoridate-treated hens. 1023 Jul 68

Diisopropyl phosphorofluoridate (DFP) is an organophosphorus ester, which produces organophosphorus ester-induced delayed neuropathy (OPIDN) in hen and other sensitive species. A single dose of DFP (1.7 mg/kg, sc.) produces mild ataxia in 7-14 days in hens, which develops into severe ataxia or paralysis with the progression of disease. OPIDN is associated with axonal swellings and degeneration of axons. This study was carried out to investigate the expression of neurofilament (NF) subunits in the spinal cord of DFP-treated hens. Hens were treated with a single dose of DFP and sacrificed 1, 5, 10, and 20 days post-treatment. Western blot analysis showed increased expression of middle molecular weight neurofilament protein (NF-M), and decreased expression of high molecular weight (NF-H) and low molecular weight (NF-L) neurofilament proteins in the 2 M urea extracts of spinal cord particulate fraction. These changes were observed within 24 h of DFP administration and persisted for 10-20 days. Thus, there was increase in the stoichiometry of NF-M:NF-L in the spinal cord of DFP-treated hens. Immunoprecipitation, cross-linking, and two-dimensional polyacrylamide gel electrophoresis showed the presence of heterodimers, but not heterotetramers, in the hen spinal cord extract. Immunohistochemical staining revealed the presence of all three NF subunits in the cytoskeletal inclusions in DFP-treated hen spinal cord cross-sections. The results suggested that each NF subunit might be accumulated by a different mechanism in the axonal aggregations of DFP-treated hen.
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PMID:Altered expression of neurofilament subunits in diisopropyl phosphorofluoridate-treated hen spinal cord and their presence in axonal aggregations. 1099 34

Diisopropyl phosphorofluoridate (DFP) is an organophosphorus ester, which produces delayed neurotoxicity (OPIDN) in hens in 7-14 days. OPIDN is characterized by mild ataxia in its initial stages and severe ataxia or paralysis in about 3 weeks. It is marked by distal swollen axons, and exhibits aggregations of neurofilaments (NFs), microtubules, proliferated smooth endoplasmic reticulum, and multivesicular bodies. These aggregations subsequently undergo disintegration, leaving empty varicosities. Previous studies in this laboratory have shown an increased level of medium-molecular weight NF (NF-M) and decreased levels of high- and low-molecular weight NF (NF-H, NF-L) proteins in the spinal cord of DFP-treated hens. The main objective of this investigation was to study the effect of DFP administration on NF subunit levels when OPIDN is prevented or potentiated by pretreatment or post-treatment with phenylmethylsulfonyl fluoride (PMSF), respectively. Hens pretreated or post-treated with PMSF were killed 1, 5, 10, and 20 days after the last treatment. The alteration in NF subunit protein levels observed in DFP-treated hen spinal cords was not observed in protected hens. Estimation of NFs in the potentiation experiments, however, showed a different pattern of alteration in NF subunit levels. The results showed that an alteration in NF subunit levels in DFP-treated hens might be related to the development of OPIDN, since these changes were suppressed in PMSF-protected hens. However, results from PMSF post-treated hen spinal cords suggested that potentiation of OPIDN by PMSF was mediated by a mechanism different from that followed by DFP alone to produce OPIDN.
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PMID:Protein levels of neurofilament subunits in the hen central nervous system following prevention and potentiation of diisopropyl phosphorofluoridate (DFP)-induced delayed neurotoxicity(1). 1175 69

Tri-ortho-cresyl phosphate (TOCP), an organophosphorus ester, is capable of producing organophosphorus ester-induced delayed neuropathy (OPIDN) in human being and sensitive animals. In the present study, adult hens were treated with TOCP by gavage at single dosage of 750 mg/kg, and sacrificed by decapitation on the corresponding time points of 1, 5, 10, and 21 day post-dosing, respectively. The tibial nerves were dissected, homogenized, and centrifuged at 100,000 xg. The level of neurofilaments protein in both pellet and supernatant fractions was determined. Western blot analysis showed a nearly depletion of NF-M and a dramatic decrease of NF-L in both fractions of tibial nerves. These changes were observed within 24h of TOCP administration and then followed by an obvious recovery. In contrast, a progressive reduction in NF-H was observed in tibial nerves of TCOP-treated hens throughout the period of experiment. With the reduction of NF-L level, the rate of NF-L degradation demonstrated a significant increase in both fractions of tibial nerves. Furthermore, the expression of mu-calpain in tibial nerves was increased following TOCP. Taken together, these results demonstrated that NFs changes occurred much earlier than the clinical appearance of ataxia in TOCP-induced delayed neuropathy, indicating that disruption of NF homeostasis in peripheral nerves might be an early molecular event in the development of OPIDN.
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PMID:Neurofilaments degradation as an early molecular event in tri-ortho-cresyl phosphate (TOCP) induced delayed neuropathy. 1942 28