Human receptor for activated protein kinase C1 associates with polyglutamine aggregates and modulates polyglutamine toxicity

Parkinson’s disease (PD) is a common movement disorder marked by the loss of dopaminergic (DA) neurons in the brain stem and the presence of intraneuronal inclusions designated as Lewy bodies (LB). The cause of neurodegeneration in PD is not clear, but it has been suggested that protein misfolding and aggregation contribute significantly to the development of the disease. Misfolded and aggregated proteins are cleared by ubiquitin proteasomal system (UPS) and autophagy lysosomal pathway (ALP). Recent studies suggested that different types of ubiquitin linkages can modulate these two pathways in the process of protein degradation. In this study, we found that co‐expression of ubiquitin can rescue neurons from α‐syn‐induced neurotoxicity in a Drosophila model of PD. This neuroprotection is dependent on the formation of lysine 48 polyubiquitin linkage which is known to target protein degradation via the proteasome. Consistent with our results that we observed in vivo, we found that ubiquitin co‐expression in the cell can facilitate cellular protein degradation by the proteasome in a lysine 48 polyubiquitin‐dependent manner. Taken together, these results suggest that facilitation of proteasomal protein degradation can be a potential therapeutic approach for PD.

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“…Deep pseudopupil assay was performed according to previous study (Berger et al. 2005; Lam et al. 2008; Wong et al.…”

Section: Methodsmentioning

confidence: 99%

The role of ubiquitin linkages on α‐synuclein induced‐toxicity in a Drosophila model of Parkinson’s disease

Lee

Wong

Lee

et al. 2009

Journal of Neurochemistry

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“…Indeed, neuronal cell death associated with transient expression of mutant Htt in cultured striatal neurons is inversely proportional to Htt aggregate formation (Arrasate et al 2004), suggesting that inclusion body formation may decrease levels of other toxic forms of Htt and promote neuronal survival. There is also evidence suggesting that oligomers precede aggregate formation and are the toxic species in HD (Lam et al 2008;Lajoie and Snapp 2010). These contradictory results in different cellular contexts and HD models have led to confusion over the toxicity of aggregates and, subsequently, over whether therapeutic approaches in HD should focus on reducing or enhancing aggregate formation.…”

mentioning

confidence: 99%

Huntingtin Aggregation Kinetics and Their Pathological Role in aDrosophilaHuntington’s Disease Model

et al. 2012

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Huntington's disease is a neurodegenerative disorder resulting from expansion of a polyglutamine tract in the Huntingtin protein. Mutant Huntingtin forms intracellular aggregates within neurons, although it is unclear whether aggregates or more soluble forms of the protein represent the pathogenic species. To examine the link between aggregation and neurodegeneration, we generated Drosophila melanogaster transgenic strains expressing fluorescently tagged human huntingtin encoding pathogenic (Q138) or nonpathogenic (Q15) proteins, allowing in vivo imaging of Huntingtin expression and aggregation in live animals. Neuronal expression of pathogenic Huntingtin leads to pharate adult lethality, accompanied by formation of large aggregates within the cytoplasm of neuronal cell bodies and neurites. Live imaging and Fluorescence Recovery After Photobleaching (FRAP) analysis of pathogenic Huntingtin demonstrated that new aggregates can form in neurons within 12 hr, while preexisting aggregates rapidly accumulate new Huntingtin protein within minutes. To examine the role of aggregates in pathology, we conducted haplo-insufficiency suppressor screens for Huntingtin-Q138 aggregation or Huntingtin-Q138-induced lethality, using deficiencies covering 80% of the Drosophila genome. We identified two classes of interacting suppressors in our screen: those that rescue viability while decreasing Huntingtin expression and aggregation and those that rescue viability without disrupting Huntingtin aggregation. The most robust suppressors reduced both soluble and aggregated Huntingtin levels, suggesting toxicity is likely to be associated with both forms of the mutant protein in Huntington's disease.

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“…Alloway was reported that the students with high level of serum copper had a cognitive problem as well as low academic achievement 36 . Lam was also confirmed the association between high serum copper levels and low cognitive performance in older adults 37 , while Salustriwas found that copper may be linked to working memory through its effects on attention 38 , and Zecca 39 was indicated that copper tends to accumulate to a higher level in brain areas associated with attention, that means, decreasing of serum copper may be a type of response to improvement of working memory.…”

Section: Discussionmentioning

confidence: 68%

Effect of temporary examination stress on ceruloplasmin, copper, and iron levels in sera of academic students

2017

Iraqi J. Public Health

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Objective: Examination stress is a common and widespread phenomenon for students. So the main aim of this study was to check the effect of temporary examination stress on some biochemical parameters in sera of academic students. Methods: A total of 55 apparently healthy undergraduate students were enrolled in this study. Blood samples were collected two times from each student, at a written exam (E-day) and at the normal day (N-day). The serum Cp concentration and Cp ferroxidase activity were measured by spectrophotometry, while total serum copper and iron ions were measured by atomic absorption technique. The results were compared between E-day and N-day. Results: Significantly decrease (P < 0.05) were found in the serum Cp concentration, Cp ferroxidase activity, and total serum copper for all students. The total serum iron was significantly decreased (P < 0.05) in the female group. Conclusion: Cp ferroxidase activity was significantly decreased in E-day compared with N-day in response to releasing iron that accumulates in the liver. It may be an indicator of increasing oxidative stress in the sera of students in examination stress; also serum copper was significantly decreased in all undergraduate students in this comparison in response to antioxidant role of Cp.

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Human receptor for activated protein kinase C1 associates with polyglutamine aggregates and modulates polyglutamine toxicity

Cited by 8 publications

References 42 publications

The role of ubiquitin linkages on α‐synuclein induced‐toxicity in a Drosophila model of Parkinson’s disease

The role of ubiquitin linkages on α‐synuclein induced‐toxicity in a Drosophila model of Parkinson’s disease

Huntingtin Aggregation Kinetics and Their Pathological Role in aDrosophilaHuntington’s Disease Model

Effect of temporary examination stress on ceruloplasmin, copper, and iron levels in sera of academic students

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