Posttranslational Modifications and Clearing of α-Synuclein Aggregates in Yeast

Popova, Blagovesta; Kleinknecht, Alexandra; Braus, Gerhard H.

doi:10.3390/biom5020617

Cited by 38 publications

(46 citation statements)

References 119 publications

(145 reference statements)

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“…Post-translational modification of proteins such as tau, α-synuclein, and HTT has been linked to regulating their abundance in cells, potentially in association with cellular clearance networks (Pennuto et al, 2009; Popova et al, 2015). As protein clearance mechanisms become impaired upon aging, modified proteins which normally would be targeted for degradation may ultimately create accumulated clearance intermediates that take on toxic properties (Orr and Zoghbi, 2007; Shao and Diamond, 2007).…”

Section: Discussionmentioning

confidence: 99%

PIAS1 Regulates Mutant Huntingtin Accumulation and Huntington’s Disease-Associated Phenotypes In Vivo

Ochaba

Monteys

O’Rourke

et al. 2016

Neuron

110

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SUMMARY The disruption of protein quality control networks is central to pathology in Huntington’s disease (HD) and other neurodegenerative disorders. The aberrant accumulation of insoluble high molecular weight protein complexes containing the Huntingtin (HTT) protein and SUMOylated protein corresponds to disease manifestation. We previously identified a HTT selective E3 SUMO ligase, PIAS1, which regulates HTT accumulation and SUMO modification in cells. Here we investigated whether PIAS1 modulation in neurons alters HD-associated phenotypes in vivo. Instrastriatal injection of a PIAS1-directed miRNA significantly improved behavioral phenotypes in rapidly progressing mutant HTT (mHTT) fragment R6/2 mice. PIAS1 reduction prevented the accumulation of mHTT, SUMO- and ubiquitin-modified proteins, increased synaptophysin levels, and normalized key inflammatory markers. In contrast, PIAS1 overexpression exacerbated mHTT-associated phenotypes and aberrant protein accumulation. These results confirm the association between aberrant accumulation of expanded polyglutamine-dependent insoluble protein species to pathogenesis and link phenotypic benefit to reduction of these species through PIAS1 modulation.

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Section: Discussionmentioning

confidence: 99%

PIAS1 Regulates Mutant Huntingtin Accumulation and Huntington’s Disease-Associated Phenotypes In Vivo

Ochaba

Monteys

O’Rourke

et al. 2016

Neuron

110

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“…; Popova et al . ). In principle, antibodies may even be raised to differentiate ‘strains’ of α‐synuclein aggregates, characterized by different conformation of the misfolded protein (Bousset et al .…”

Section: Measuring Aggregates Of α‐Synuclein – Biochemical Methodsmentioning

confidence: 97%

Cellular models for Parkinson's disease

Falkenburger

Saridaki

Dinter

2016

Journal of Neurochemistry

106

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Developing new therapeutic strategies for Parkinson's disease requires cellular models. Current models reproduce the two most salient changes found in the brains of patients with Parkinson's disease: The degeneration of dopaminergic neurons and the existence of protein aggregates consisting mainly of a-synuclein. Cultured cells offer many advantages over studying Parkinson's disease directly in patients or in animal models. At the same time, the choice of a specific cellular model entails the requirement to focus on one aspect of the disease while ignoring others. This article is intended for researchers planning to use cellular models for their studies. It describes for commonly used cell types the aspects of Parkinson's disease they model along with technical advantages and disadvantages. It might also be helpful for researchers from other fields consulting literature on cellular models of Parkinson's disease. Important models for the study of dopaminergic neuron degeneration include Lund human mesencephalic cells and primary neurons, and a case is made for the use of nondopaminergic cells to model pathogenesis of non-motor symptoms of Parkinson's disease. With regard to a-synuclein aggregates, this article describes strategies to induce and measure aggregates with a focus on fluorescent techniques. Keywords: Dementia with Lewy bodies, FRET, non-motor symptoms.This article is part of a special issue on Parkinson disease. General remarks about models for Parkinson's diseaseParkinson's disease (PD) is a common neurodegenerative disease. Life expectancy is reduced in PD patients (Macleod et al. 2014), and there is currently no causal treatment option. Developing a new therapeutic strategy requires understanding the pathogenesis of the disease and testing interventions that could have beneficial effects. Both require models, since the use of PD patients is limited by heterogeneity of disease burden, slow progression, technical obstacles and of course ethical considerations. Current models of PD only partially reproduce the disease for two main reasons. First, we do not know what causes sporadic PD and therefore cannot reproduce the entire pathogenesis in a model. Second, we want a model that unlike PD itself develops pathology quickly and reliably. In addition, we want to be able to monitor and manipulate the model easily, and test many approaches simultaneously. For these reasons, a useful model needs to differ from PD in critical aspects. Models can represent aspects of PD found on the level of behaviour, electrical activity, individual cells and/or molecules. The choice of model will depend on the aspect of the disease we want to study and the kind of therapy we want to develop. If we want to develop a medication, it will have a molecular target thus a cellular model can be a good starting point.As compared to animal models, cellular models develop pathology more quickly, are less costly and do not require ethical approval. Genetic or pharmacological manipulations and time-lapse imaging are easier and m...

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“…Thus, intensive researches focus on how to prevent or eliminate the aggregation of α-synuclein. Study show that ubiquitin proteasome system (UPS) is responsible for degrading monoubiquitinated α-synuclein, while macroautophagy is for removing deubiquitinated α-synuclein [41, 42]. Further study demonstrates, in normal condition, α-synuclein is mainly degraded by UPS [43].…”

Section: Pd-related Genes Are Involved In Dysregulation Of Autophagymentioning

confidence: 99%

Dysregulation of autophagy and mitochondrial function in Parkinson’s disease

Bao

Abraham

Gao

et al. 2016

Transl Neurodegener

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Parkinson’s disease (PD) is the second most common neurodegenerative disease. Increasing evidence supports that dysregulation of autophagy and mitochondrial function are closely related with PD pathogenesis. In this review, we briefly summarized autophagy pathway, which consists of macroautophagy, microautophagy and chaperone-mediated autophagy (CMA). Then, we discussed the involvement of mitochondrial dysfunction in PD pathogenesis. We specifically reviewed the recent developments in the relationship among several PD related genes, autophagy and mitochondrial dysfunction, followed by the therapeutic implications of these pathways. In conclusion, we propose that autophagy activity and mitochondrial homeostasis are of high importance in the pathogenesis of PD. Better understanding of these pathways can shed light on the novel therapeutic methods for PD prevention and amelioration.

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Posttranslational Modifications and Clearing of α-Synuclein Aggregates in Yeast

Cited by 38 publications

References 119 publications

PIAS1 Regulates Mutant Huntingtin Accumulation and Huntington’s Disease-Associated Phenotypes In Vivo

PIAS1 Regulates Mutant Huntingtin Accumulation and Huntington’s Disease-Associated Phenotypes In Vivo

Cellular models for Parkinson's disease

Dysregulation of autophagy and mitochondrial function in Parkinson’s disease

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