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)

We reported a 65-year-old man whose sister was suffering from HTLV-I-associated myelopathy (HAM) and who presented slowly progressive spastic paraparesis, sensory disturbance in the feet, tremors and cerebellar ataxia. He was also positive for serum anti-HTLV-I antibody. He first showed a head tremor at the age of 3 years. He developed a spastic and ataxic gait when aged 15 years, and it became difficult for him to walk at the age of 50 years. Examination at 65 years showed a spastic and ataxic gait and scanning speech. Hyper-reflexia and Bahinski's signs were observed. Sensation in the feet was decreased. The anti-HTLV-I antibody titer in the serum was 1:512 by the PA method, and Western blot analysis revealed bands of P19, P24, P28 and P32. Examination of the cerebrospinal fluid (CSF), including oligoclonal bands, gave normal results. The CSF was negative for anti-HTLV-I antibody. CT and MRI of the head showed cerebellar atrophy. His sister was 60 years old. She had developed a spastic gait at the age of 15 years. Sensory defects and bladder dysfunction developed when aged 35 years. Hyper-reflexia, Babinski's sign and foot clonus were observed. Sensation in the feet was decreased. The urinary residual volume was increased. Ataxia was not observed. The anti-HTLV-I antibody titer in the serum was 1:8,192 by the PA method, and Western blot analysis revealed bands of p24, p28 and p32. Examination of the CSF, including oligoclonal bands, gave only normal results.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Spastic paraparesis and sensory disturbance improved by prednisolone therapy]. 139 32

Astrocytes have been proposed to have multiple roles in the development and maintenance of the vertebrate CNS. To facilitate documentation of these roles, we designed a transgene to enable their ablation at selectable times. The transgene consists of the coding region for the herpes simplex virus-thymidine kinase (HSV-TK) under the control of the human glial fibrillary acidic protein gene promoter. The HSV-TK is innocuous but converts the antiherpetic agent ganciclovir (GCV) to a toxic product that interferes with DNA replication in proliferating cells. In a developmental study, transgenic mice were treated with GCV during the first postnatal week, with evaluation at P19. Treated mice displayed severe ataxia. Histological examination revealed disrupted astrocyte development, particularly in the cerebellum, with marked secondary effects on other cell types. Cerebellar defects included a loss in the numbers of astrocytes and an overall reduction in cerebellar size and disruption of the normally well defined cellular layers. Radial glia were disordered, Purkinje cells were ectopically distributed and displayed abnormal dendritic trees, and granule cells were markedly depleted. These effects were more severe in animals treated on postnatal day 1 versus treatment at day 5. A major factor causing granule cell death was excitotoxicity attributable to activation of NMDA receptors. These results suggest a critical role for astrocytes in cerebellar development.
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PMID:Conditional ablation of cerebellar astrocytes in postnatal transgenic mice. 882 29

We have established that the gene AF4, which had long been recognized as disrupted in childhood leukemia, also plays a role in the CNS. Af4 is mutated in the robotic mouse that is characterized by ataxia and Purkinje cell loss. To determine the molecular basis of this mutation, we carried out a yeast two-hybrid screen and show that Af4 binds the E3 ubiquitin ligases Drosophila seven in absentia (sina) homologues (Siah)-1a and Siah-2 in the brain. Siah-1a and Af4 are expressed in Purkinje cells and colocalize in the nucleus of human embryonic kidney 293T and P19 cells. In vitro binding assays and coimmunoprecipitation reveal a significant reduction in affinity between Siah-1a and robotic mutant Af4 compared with wild-type, which correlates with the almost complete abolition of mutant Af4 degradation by Siah-1a. These data strongly suggest that an accumulation of mutant Af4 occurs in the robotic mouse due to a reduction in its normal turnover by the proteasome. A significant increase in the transcriptional activity of mutant Af4 relative to wild-type was obtained in mammalian cells, suggesting that the activity of Af4 is controlled through Siah-mediated degradation. Another member of the Af4 family, Fmr2, which is involved in mental handicap in humans, binds Siah proteins in a similar manner. These results provide evidence that a common regulatory mechanism exists that controls levels of the Af4/Fmr2 protein family. The robotic mouse thus provides a unique opportunity to understand how these proteins play a role in disorders as diverse as leukemia, mental retardation, and neurodegenerative disease.
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PMID:Mediation of Af4 protein function in the cerebellum by Siah proteins. 1545 19

Human Cayman ataxia and mouse or rat dystonia are linked to mutations in the genes ATCAY (Atcay) that encode BNIP-H or Caytaxin, a brain-specific member of the BNIP-2 family. To explore its possible role(s) in neuronal function, we used protein precipitation and matrix-assisted laser desorption/ionisation mass spectrometry and identified kidney-type glutaminase (KGA) as a novel partner of BNIP-H. KGA converts glutamine to glutamate, which could serve as an important source of neurotransmitter. Co-immunoprecipitation with specific BNIP-H antibody confirmed that endogenous BNIP-H and KGA form a physiological complex in the brain, whereas binding studies showed that they interact with each other directly. Immunohistochemistry and in situ hybridisation revealed high BNIP-H expression in hippocampus and cerebellum, broadly overlapping with the expression pattern previously reported for KGA. Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals. It also reduced the steady-state levels of glutamate by inhibiting KGA enzyme activity. These results strongly suggest that through binding to KGA, BNIP-H could regulate glutamate synthesis at synapses during neurotransmission. Thus, loss of BNIP-H function could render glutamate excitotoxicity or/and deregulated glutamatergic activation, leading to ataxia, dystonia or other neurological disorders.
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PMID:Brain-specific BNIP-2-homology protein Caytaxin relocalises glutaminase to neurite terminals and reduces glutamate levels. 1689 18

Senataxin is encoded by the SETX gene and is mainly involved in two different neurodegenerative diseases, the dominant juvenile form of amyotrophic lateral sclerosis type 4 and a recessive form of ataxia with oculomotor apraxia type 2. Based on protein homology, senataxin is predicted to be a putative DNA/RNA helicase, while senataxin interactors from patients' lymphoblast cell lines suggest a possible involvement of the protein in different aspects of RNA metabolism. Except for an increased sensitivity to oxidative DNA damaging agents shown by some ataxia with neuropathy patients' cell lines, no data are available about possible functional consequences of dominant SETX mutations and no studies address the function of senataxin in neurons. To start elucidating the physiological role of senataxin in neurons and how disease-causing mutations in this protein lead to neurodegeneration, we analysed the effect of senataxin on neuronal differentiation in primary hippocampal neurons and retinoic acid-treated P19 cells by modulating the expression levels of wild-type senataxin and three different dominant mutant forms of the protein. Wild-type senataxin overexpression was required and sufficient to trigger neuritogenesis and protect cells from apoptosis during differentiation. These actions were reversed by silencing of senataxin. In contrast, overexpression of the dominant mutant forms did not affect the regular differentiation process in primary hippocampal neurons. Analysis of the cellular pathways leading to neuritogenesis and cytoprotection revealed a role of senataxin in modulating the expression levels and signalling activity of fibroblast growth factor 8. Silencing of senataxin reduced, while overexpression enhanced, fibroblast growth factor 8 expression levels and the phosphorylation of related target kinases and effector proteins. The effects of senataxin overexpression were prevented when fibroblast growth factor 8 signalling was inhibited, while exogenous fibroblast growth factor 8 reversed the effects of senataxin silencing. Overall, these results reveal a key role of senataxin in neuronal differentiation through the fibroblast growth factor 8 signalling and provide initial molecular bases to explain the neurodegeneration associated with loss-of-function mutations in senataxin found in recessive ataxia. The lack of effect on neuritogenesis observed with the overexpression of the dominant mutant forms of senataxin apparently excludes a dominant negative effect of these mutants while favouring haploinsufficiency as the pathogenic mechanism implicated in the amyotrophic lateral sclerosis 4-related degenerative condition. Alternatively, a different protein function, other than the one involved in neuritogenesis, may be implicated in these dominant degenerative processes.
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PMID:Senataxin modulates neurite growth through fibroblast growth factor 8 signalling. 2157 11