Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A patient with progressive anomia and alexia with agraphia for kanji (Japanese morphograms) is described. The patient showed a deficit in single-word comprehension and on-reading (a type of reading that conveys phonetic value) dominance in kanji reading, i.e. on-preceding (pronouncing first with on-reading, irrespective of its preferred reading) and kun-deletion (inability to recall and recognize kun-reading [another type of reading that conveys meaning]) when reading a single-character kanji. These features were due to loss of lexico-semantic information and thus the patient was regarded as having progressive Gogi (word-meaning) aphasia by Imura, a Japanese manifestation of semantic dementia. Macroscopically, neuropathological examination disclosed atrophy of the left frontotemporal lobe with accentuation in the anterior portion of the temporal lobe. Histologically, there was neuronal loss in the cerebral cortex, hippocampus, parahippocampal gyrus, amygdala, caudate nucleus, and putamen. Ubiquitin-immunoreactive neuronal inclusions were present in the hippocampal dentate granular cells. This case demonstrates that progressive Gogi aphasia is semiologically identical to semantic dementia, and our patient clinicopathologically resembled those of Rossor et al. [Rossor, M.N., Revesz, T., Lantos, P.L., Warrington, E.K. Semantic dementia with ubiquitin-positive tau-negative inclusion bodies. Brain 2000; 123: 267-76.] and Hodges et al. [Hodges, J.R., Davies, R.R., Xuereb, J.H., Casey, B., Broe, M., Bak, T.H., et al. Clinicopathological correlates in frontotemporal dementia. Ann Neurol 2004; 56: 399-406.].
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PMID:Ubiquitin-positive frontotemporal lobar degeneration presenting with progressive Gogi (word-meaning) aphasia. A neuropsychological, radiological and pathological evaluation of a Japanese semantic dementia patient. 1704 99

We report a case of a 68-year-old right-handed man with sporadic amyotrophic lateral sclerosis (ALS) and argyrophilic grain disease (AGD) having a 22-month duration. His initial symptoms were dysarthria and swallowing difficulty at the age of 67. Subsequently bulbar palsy and pyramidal signs developed. His cognitive functions including face recognition, personality, and behavior were not changed compared with that of before the disease onset. However, magnetic resonance imaging disclosed severe right side-predominant temporal atrophy. The neurological diagnosis was bulbar type ALS. Pathological examination disclosed histological evidence of ALS, including loss of Betz cells and lower motor neurons, corticospinal tract degeneration, and Bunina bodies. In addition, severe neuronal loss in the bilateral temporal cortex with an anterior gradient was found. Ubiquitin-positive inclusions were encountered in the spinal anterior horn cells and hippocampal dentate gyrus, while few ubiquitin-positive inclusions were noted in the affected temporal cortex. The amygdala, especially the basolateral nuclear group, was severely affected by neuronal loss with tissue rarefaction. Moderate neuronal loss was encountered in the parahippocampal gyrus, and to a lesser degree, in the ambient gyrus. Unexpectedly, many argyrophilic grains, coiled bodies, tau-positive bush-like astrocytes, pretangles, and ballooned neurons were found in the limbic system and temporal cortex. In the hippocampus, selective tau accumulation with minor neurofibrillary changes was observed in CA2 neurons. The present case suggests that (i) ALS and AGD do rarely coexist, and (ii) when ALS patients have severe temporal atrophy, not only ALS with dementia but also concurrent AGD should be considered in the differential diagnosis.
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PMID:Coexistence of amyotrophic lateral sclerosis and argyrophilic grain disease: a non-demented autopsy case showing circumscribed temporal atrophy and involvement of the amygdala. 1802 74

Ubiquitin-positive, tau-negative, frontotemporal dementia (FTD) is caused by null mutations in progranulin (PGRN; HUGO gene symbol GRN), suggesting a haploinsufficiency mechanism. Since whole gene deletions also lead to the loss of a functional allele, we performed systematic quantitative analyses of PGRN in a series of 103 Belgian FTD patients. We identified in one patient (1%) a genomic deletion that was absent in 267 control individuals. The deleted segment was between 54 and 69 kb in length and comprised PGRN and two centromeric neighboring genes RPIP8 (HUGO gene symbol RUNDC3A) and SLC25A39. The patient presented clinically with typical FTD without additional symptoms, consistent with haploinsufficiency of PGRN being the only gene contributing to the disease phenotype. This study demonstrates that reduced PGRN in absence of mutant protein is sufficient to cause neurodegeneration and that previously reported PGRN mutation frequencies are underestimated.
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PMID:Progranulin locus deletion in frontotemporal dementia. 1815 29

Ubiquitin is a highly conserved protein involved in many important cellular processes, such as cell surface receptor signaling, endocytosis and protein degradation. Since ubiquitin plays a key role in the pathomechanisms of many neurodegenerative diseases, we immunohistochemically analyzed its expression in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). CADASIL is a heritable vascular dementia characterized by degeneration of the vascular smooth muscle cells (VSMC) caused by mutations in the notch 3 gene. In CADASIL, there is abnormal accumulation of the Notch 3 extracellular domain on blood vessels, but the molecular pathways linking notch 3 mutations to degeneration of the VSMC are, as yet, poorly understood. We studied human brain and skin biopsy specimens, and observed increased ubiquitin expression on structures primarily affected by the pathological process in CADASIL: the VSMC and vascular lamina media, and also large ballooned macrophages. Ultrastructurally, we noted that pathognomonic CADASIL deposits of granular osmiophilic material were often located inside indentations in the VSMC membrane that resembled endocytic vesicles. We suggest that in CADASIL, damage to the VSMC may be associated with aberrant ubiquitin-dependent endocytosis of the Notch 3 ligand, and increased accumulation of ubiquitin on the vessel wall may be a manifestation of this aberration.
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PMID:Is the increased expression of ubiquitin in CADASIL syndrome a manifestation of aberrant endocytosis in the vascular smooth muscle cells? 1831

Genetic studies have led to major discoveries in the pathogenesis of various neurodegenerative diseases. Ubiquitin-positive familial frontotemporal dementia was recently found to be caused by mutations in the progranulin gene (PGRN), and the major constituent of the inclusions, TDP-43, was subsequently identified. The tau gene (MAPT) causes frontotemporal dementia with parkinsonism linked to chromosome 17. In Parkinson disease, LRRK2 mutations have emerged as a major cause of both familial and sporadic forms, adding to the previously known genes SNCA,PRKN,DJ1 and PINK1. Several genes have been implicated in Alzheimer disease, including the APP gene and the PSEN genes. Recently, variants in the sortilin-related receptor 1 gene, SORL1, were associated with Alzheimer disease.
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PMID:Etiology and pathophysiology of frontotemporal dementia, Parkinson disease and Alzheimer disease: lessons from genetic studies. 1832 68

TDP-43 (43-kDa TAR DNA-binding domain protein) is a major constituent of ubiquitin-positive cytoplasmic aggregates present in neurons of patients with fronto-temporal lobular dementia and amyotrophic lateral sclerosis (ALS). The pathologic significance of TDP-43 aggregation is not known; however, dominant mutations in TDP-43 cause a subset of ALS cases, suggesting that misfolding and/or altered trafficking of TDP-43 is relevant to the disease process. Here, we show that the presenilin-binding protein ubiquilin 1 (UBQLN) plays a role in TDP-43 aggregation. TDP-43 interacted with UBQLN both in yeast and in vitro, and the carboxyl-terminal ubiquitin-associated domain of UBQLN was both necessary and sufficient for binding to polyubiquitylated forms of TDP-43. Overexpression of UBQLN recruited TDP-43 to detergent-resistant cytoplasmic aggregates that colocalized with the autophagosomal marker, LC3. UBQLN-dependent aggregation required the UBQLN UBA domain, was mediated by non-overlapping regions of TDP-43, and was abrogated by a mutation in UBQLN previously linked to Alzheimer disease. Four ALS-associated alleles of TDP-43 also coaggregated with UBQLN, and the extent of aggregation correlated with in vitro UBQLN binding affinity. Our findings suggest that UBQLN is a polyubiquitin-TDP-43 cochaperone that mediates the autophagosomal delivery and/or proteasome targeting of TDP-43 aggregates.
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PMID:Potentiation of amyotrophic lateral sclerosis (ALS)-associated TDP-43 aggregation by the proteasome-targeting factor, ubiquilin 1. 1911 76

The aim of the present study was to examine the expression of synphilin-1, alpha-synuclein, and tyrosine hydroxylase in human elderly brains and the incidence of Marinesco bodies (MBs, intranuclear inclusions) in the neuromelanin-containing substantia nigra neurons. The brains of twenty-two individuals without clinical signs and symptoms of parkinsonism and dementia and an additional two parkinsonian patients were dissected and subjected to histopathological examination and western blotting. Ubiquitin-positive and agr;-synuclein-negative MBs were found in 0.84-9.45% of the nigral neurons from brains of 15 healthy individuals and both parkinsonian patients. The frequency of pigmented nigral neurons containing MBs was positively correlated with age. The levels of tyrosine hydroxylase in the caudate nucleus and putamen decreased with age, and were inversely correlated with the MB frequency. The level of synphilin-1 in the caudate nucleus was positively correlated both with age and the MBs. Additionally, the MB appearance was correlated with synphilin-1 level in the substantia nigra. No significant correlation between alpha-synuclein expression and age or MBs was found. Our results suggest that synphilin-1 expression increases with aging. Further studies on expression of this protein in elderly brains are warranted.
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PMID:Increased synphilin-1 expression in human elderly brains with substantia nigra Marinesco bodies. 1921 84

Ubiquitin immunoreactive (UBQ-ir) inclusions were present to variable extents in the inferior olivary nucleus (ION) in 37/48 (77%) patients with frontotemporal lobar degeneration (FTLD), in 10/11 (91%) patients with motor neurone disease (MND), in 5/5 (100%) patients with Alzheimer's disease (AD), 5/7 (71%) patients with dementia with Lewy bodies, 13/19 (68%) patients with Parkinson's disease, 11/11(100%) patients with Progressive Supranuclear Palsy, 2/6 (33%) patients with Multisystem Atrophy, 1/3 (33%) patients with Huntington's disease and in 14/14 (100%) normal elderly control subjects. In FTLD, UBQ-ir inclusions were present in 26/32 (81%) patients with FTLD-U, in 10/15 (67%) patients with tauopathy, and in the single patient with Dementia Lacking Distinctive Histology. In 13 FTLD-U patients, and in a single AD and in 2 MND patients, the UBQ-ir inclusions had a rounded, spicular or skein-type appearance, and these were also TDP-43 immunoreactive (TDP-43-ir). In all other affected patients in all diagnostic groups, and in control subjects, the UBQ-ir neuronal cytoplasmic inclusions (NCI) were of a conglomerated type, resembling a cluster of large granules or globules, but were never TDP-43-ir. In 3 of the 13 FTLD-U patients with spicular NCI, conglomerated NCI were also present but in separate cells. Double-labelling immunohistochemistry, and confocal microscopy, for UBQ and TDP-43 confirmed that only the spicular UBQ-ir inclusions in patients with FTLD-U, AD and MND contained TDP-43, though in these patients there were occasional TDP-43 immunoreactive inclusions that were not UBQ-ir. Nuclear TDP-43 immunoreactivity was absent in ION in FTLD-U, AD or MND when TDP-43 cytoplasmic inclusions were present, but remained in neurones with UBQ-ir, TDP-43 negative inclusions. The target protein within the UBQ-ir, TDP-43-negative inclusions remains unknown, but present studies indicate that this is not tau, neurofilament or internexin proteins. These TDP-43 negative, UBQ-ir inclusions appear to be more related to ageing than neurodegeneration, and are without apparent diagnostic significance. The pathophysiological mechanism leading to their formation, and any consequences their presence may have on nerve cell function, remain unknown.
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PMID:TDP-43 in ubiquitinated inclusions in the inferior olives in frontotemporal lobar degeneration and in other neurodegenerative diseases: a degenerative process distinct from normal ageing. 1933 Mar 39

The history and classification of frontotemporal lobar degeneration (FTLD) are reviewed in this paper. After Pick's descriptions, there are confusions regarding the classification of the clinical syndromes and the underlying histological changes of frontotemporal lobe degeneration of the non-Alzheimer type. In 1994, the Lund and Manchester groups proposed clinical and neuropathological criteria for the classification of frontotemporal dementia (FTD); frontal lobe degeneration type, Pick-type, and motor neuron disease (MND) type. Ubiquitin-positive and tau-negative inclusions in the extra-motor neurons were characteristic of MND type and were first described by us. In 1996 and 1998, Neary et al. proposed the concept of FTLD to facilitate diagnosis and provide diagnostic criteria for 3 clinical syndromes associated with FTLD, namely, FTD, progressive nonfluent aphasia, and semantic dementia. In 2001, an international group of clinical and basic scientists reassessed the clinical and neuropathological criteria for the diagnosis of FTD and recommended revised neuropathological criteria for diagnosis. In 2007, Cairns et al. proposed another version of the criteria for pathological diagnosis of the neurodegenerative group of diseases termed as FTLD on the basis of the recent advances in molecular genetic, biochemical, and neuropathological studies. According to these criteria, FTLD is mainly divided into 2 groups-tauopathies and TDP-43 proteinopathies-on the basis of immunohistological methods.
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PMID:[History and classification of frontotemporal lobar degeneration]. 1993 76

Linkage analysis identified a region on chromosome 9p associated with Frontotemporal Lobar Degeneration (FTLD). A detailed analysis of candidate genes lying in this region demonstrated an association with Ubiquitin Associated Protein (UBAP)1. The distribution of five Single Nucleotide Polymorphisms (SNPs) located in the chromosome 9 haplotype identified via linkage analysis, including UBAP1 rs7018487, UBAP2 rs1785506 and rs307658, and KIF24 rs17350674 and rs10814083, has been determined in a population of 284 patients diagnosed with FTLD, including 245 with behavioural variant Frontotemporal Dementia (bvFTD), 23 with Progressive Aphasia and 16 with Semantic Dementia, compared with 318 age-matched controls. A statistically significant increased frequency of the KIF24 rs17350674 AA genotype was observed in patients compared with controls (7.4 versus 2.5%; P=0.0068, OR: 3.63, CI: 1.58-8.35). Considering each syndrome separately, similar results where obtained in bvFTD versus controls (7.7 versus 2.5%, P=0.005, OR: 3.26, CI: 1.40-7.57). Stratifying for gender, a statistically significant increased genotypic frequency was observed in female patients as compared with female controls (8.9 versus 2.5%, P=0.008, OR: 3.85, CI: 1.36-10.93). In silico analysis predicted that the substitution from W to L caused by the rs17350674 affects protein function (P<0.05). The KIF24 rs17350674 polymorphism likely acts as a risk factor for sporadic FTLD, but a replication study would be needed to confirm these preliminary findings.
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PMID:Is KIF24 a genetic risk factor for Frontotemporal Lobar Degeneration? 2067 Jun 73


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