Ubiquitin is associated with abnormal cytoplasmic filaments characteristic of neurodegenerative diseases.

Manetto, Valeria; Perry, George; Tabaton, Massimo; Mulvihill, Paul; Fried, Victor A.; Smith, Howard R.; Autilio-Gambetti, L.

doi:10.1073/pnas.85.12.4501

Cited by 164 publications

(65 citation statements)

References 49 publications

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“…32 In neurodegenerative diseases, SQSTM1 and ubiquitinated proteins are usually increased and associated with neuronal inclusion. [33][34][35] In this study, the polyubiquitinated inclusion body deposits in the cytoplasm are repeatedly observable in the scrapieinfected hamsters' brains, which are coincident with a previous report, 23 but the levels of autophagic substrates SQSTM1 and polyubiquitinated proteins in the brains of TSEs are obviously downregulated as incubation times increase. The reduction of polyubiquinated proteins in TSE brains contradicts a previous report 36 in which the levels of ubiquitinated proteins increase in the brains of scrapie-infected mice when measured by an indirect enzyme-linked immunosorbent assay (ELISA).…”

Section: Discussionsupporting

confidence: 59%

Activation of the macroautophagic system in scrapie-infected experimental animals and human genetic prion diseases

Tian

Wang

et al. 2012

Autophagy

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Section: Discussionsupporting

confidence: 59%

Activation of the macroautophagic system in scrapie-infected experimental animals and human genetic prion diseases

Tian

Wang

et al. 2012

Autophagy

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“…In some diseases ubiquitin-conjugated abnormal proteins are accumulated in the cell (Manetto et al, 1988;Leigh et al, 1989). Recently, prolonged loss of ubiquitin-like immunoreactivity (UIR) and subsequent neuronal death after ischemia in the CAI neurons have been reported, and it has been suggested that nonrecovery of UIR might reflect neuronal cell death (Magnusson and Wieloch, 1989).…”

Section: Introductionmentioning

confidence: 99%

Changes in ubiquitin and ubiquitin-protein conjugates in the CA1 neurons after transient sublethal ischemia

Hayashi

Takada

Matsuda

1991

Molecular and Chemical Neuropathology

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ABSTRACTlibiquitin is involved in the degradation of denatured proteins in the recovery process after various stresses. To clarify the different responses of the ubiquitin system in the hippocampal neurons after ischemia, we chose 7.5 min of sublethal forebrain ischemia in the rat. After 7.5 min of ischemia, ubiquitin-like immunoreactivity (UIR) in most of the hippocampal pyramidal cells, except for the interneurons, diminished after 3 h of reperfusion, but enhanced UIR and subsequent recovery of UIR were observed in the different hippocampal regions after 24 h of reperfusion. The most prolonged recovery of UIR in the hippocampal cells was observed in the CAl neurons after 72 h of reperfusion. Immunoblot analysis of the proteins extracted from CAI region showed that high-mol-wt ubiquitin conjugates (HMWUC) above 40 kDa increased, whereas free ubiquitin and ubiquitinated histone 2A decreased slightly after 4 h and 24 h of reperfusion. At 72 h of reperfusion, HMWUC decreased to the original level and free ubiquitin slightly increased beyond the control level. These results suggested that (1) diminished UIR does not always mean depletion of entire ubiquitin-protein conjugates; (2) even after sublethal ischemia, damaged proteins in the CAI neurons may increase, and it may take a long time for elimination of these proteins.

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“…The pathological inclusions are commonly found in neurodegenerative diseases in susceptible population of remaining neurons and the presence of such inclusions could indicate dysfunctional cells. Intracytoplasmic Lewy body inclusion is characteristic of PD and the Lewy bodies contain ␣-synuclein and ubiquitin (37)(38)(39)(40)(41). Therefore, we stained midbrain sections from 6-month-(not shown) and 11-month-old (Fig.…”

Section: Dj-1 Null Mice Did Not Show Loss Of Sn Dopamine Neurons or Omentioning

confidence: 99%

Age-dependent Motor Deficits and Dopaminergic Dysfunction in DJ-1 Null Mice

Chen

Cagniard

Mathews

et al. 2005

Journal of Biological Chemistry

237

171

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Mutations in the DJ-1 gene were recently identified in an autosomal recessive form of early-onset familial Parkinson disease. Structural biology, biochemistry, and cell biology studies have suggested potential functions of DJ-1 in oxidative stress, protein folding, and degradation pathways. However, animal models are needed to determine whether and how loss of DJ-1 function leads to Parkinson disease. We have generated DJ-1 null mice with a mutation that resembles the large deletion mutation reported in patients. Our behavioral analyses indicated that DJ-1 deficiency led to age-dependent and taskdependent motoric behavioral deficits that are detectable by 5 months of age. Unbiased stereological studies did not find obvious dopamine neuron loss in 6-month-and 11-month-old mice. Neurochemical examination revealed significant changes in striatal dopaminergic function consisting of increased dopamine reuptake rates and elevated tissue dopamine content. These data represent the in vivo evidence that loss of DJ-1 function alters nigrostriatal dopaminergic function and produces motor deficits.Mutations in DJ-1 were recently identified in an autosomal recessive form of early-onset familial Parkinson disease (PD) 1 (1). The first reported mutation involves one large deletion of the first 5 exons and part of the promoter and another mutation was a missense mutation (L166P) that might cause instability of the DJ-1 protein by preventing it from folding properly and forming homodimers (2-5). Since this first report, a number of other mutations of DJ-1 including deletion mutations, point mutations, and a frameshift mutation have been found to cause PD (6 -10). These studies suggest that the loss of the normal function of DJ-1 leads to PD.However, the nature of the normal function of DJ-1 and the mechanism by which DJ-1 deficiency leads to PD are not well established. Studies prior to the report of its association with PD suggested that DJ-1 might play a role in oncogenesis (11), male fertility (12, 13), control of protein-RNA interaction (14), and in modulating androgen receptor transcription activity (15,16). In addition, the DJ-1 protein was shown to be responsive to oxidation (17, 18), suggesting a potential role in oxidative stress, a process often implicated in PD. Studies on PD-linked DJ-1 mutations indicate that wild-type, but not mutant, DJ-1 protects cells from oxidative stress (19 -21). Canet-Aviles et al. (22) reported that oxidation of the Cys 106 residue in DJ-1 could lead to its relocalization in mitochondria and protect cells from mitochondrial damage. Structurally, DJ-1 closely resembles the members of the ThiJ/PfpI family that have protease and chaperone activities (23-27). Recent biochemical studies suggested that DJ-1 might have protease (5) and redox-dependent chaperone activities (28). Therefore, putative functions of DJ-1 seem to converge on the common pathogenesis of PD implicated in other genetic and sporadic forms of PD.Despite those new insights into the biochemical and cellular functions of DJ-1, th...

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Ubiquitin is associated with abnormal cytoplasmic filaments characteristic of neurodegenerative diseases.

Abstract: Several degenerative diseases of the nervous system are characterized by the presence of neuronal inclusions. Most

Cited by 164 publications

References 49 publications

Activation of the macroautophagic system in scrapie-infected experimental animals and human genetic prion diseases

Activation of the macroautophagic system in scrapie-infected experimental animals and human genetic prion diseases

Changes in ubiquitin and ubiquitin-protein conjugates in the CA1 neurons after transient sublethal ischemia

Age-dependent Motor Deficits and Dopaminergic Dysfunction in DJ-1 Null Mice

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