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

Several causal missense mutations in protein kinase C gamma (gamma PKC) gene have been found in spinocerebellar ataxia type 14 (SCA14), an autosomal dominant neurodegenerative disease. We previously demonstrated that mutant gamma PKC found in SCA14 is susceptible to two types of aggregation, cytoplasmic dot-like and perinuclear massive aggregation, and causes cell death in Chinese hamster ovary cells. Long-term time-lapse imaging revealed that firstly accumulated dot-like aggregation of mutant gamma PKC-green fluorescent protein (GFP) gradually formed perinuclear massive aggregations, followed by cell death. However, it remains unclear how aggregate formation of mutant gamma PKC causes cell death. In the present study, we examined whether these mutant aggregations affect the ubiquitin-proteasome system (UPS) and endoplasmic reticular (ER) stress. Two mutant gamma PKC-GFPs (S119P and G128D) were strongly ubiquitinated, and dot-like aggregations of these mutants were ubiquitin-positive and colocalized with proteasome 20S. Furthermore, proteasome activity in cells with aggregates, especially massive ones, was significantly decreased. Aggregate formation of mutant gamma PKC-GFP induced phosphorylation of PERK (PKR-like ER kinase) and nuclear expression of CHOP (C/EBP homologous protein), hallmarks of ER stress and subsequently activated caspase-3. These results indicate that aggregate formation of mutant gamma PKC found in SCA14 impairs UPS and induces ER stress, leading to apoptotic cell death.
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PMID:Aggregate formation of mutant protein kinase C gamma found in spinocerebellar ataxia type 14 impairs ubiquitin-proteasome system and induces endoplasmic reticulum stress. 1800 63

A 74-year-old woman with a diffuse large B-cell lymphoma was treated with rituximab and CHOP chemotherapy. After three cycles of chemotherapy she developed progressive symptoms of motor imbalance, fatigue, weight loss and impaired cognitive function, which was interpreted as toxicity of the CHOP chemotherapy. The sixth cycle CHOP chemotherapy was withheld and three additional cycles of rituximab were given. Two weeks later, neurological symptoms appeared, including abducens nerve palsy of her left eye, ataxia and hemiparesis of her right body. MRI of the brain revealed two hyperintense lesions on T2-weighted and fluid-attenuated inversion recovery images without oedema or gadolinium enhancement. A PCR on John Cunningham (JC) virus DNA in cerebrospinal fluid was negative, but subsequent brain biopsy diagnosed progressive multifocal leukoencephalopathy (PML). She rapidly deteriorated and died. Awareness of PML during immunosuppressive therapy can be lifesaving, since only immune reconstitution can prevent mortality in these patients.
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PMID:Progressive multifocal leukoencephalopathy during treatment with rituximab and CHOP chemotherapy in a patient with a diffuse large B-cell lymphoma. 2335 83

A 67-year-old male was transferred to our hospital with diplopia, decreased deep tendon reflex and ataxia. He had been suspected Fisher syndrome because of previous upper respiratory tract infection. A cerebrospinal fluid examination showed marked hypoglycorrhachia, pleocytosis and elevated protein, and cytological examination suggested malignant lymphoma. Abdominal computed tomography revealed a left adrenal mass. A biopsy of the left adrenal mass revealed diffuse large B-cell lymphoma. He was treated with a combination of R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, oncovin and prednisolone) and intrathecal administration of methotrexate, cytarabine and prednisolone. Neurological symptoms were gradually improved. Malignancy should be considered in addition to bacterial, fungal or tuberculous meningitis in a case with marked hypoglycorrhachia.
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PMID:[A case of secondary central nervous system lymphoma presenting marked hypoglycorrhachia]. 3114 12