Ubiquitin-dependent proteolysis in yeast cells expressing neurotoxic proteins

Abstract

Critically impaired protein degradation is discussed to contribute to neurodegenerative disorders, including Parkinson's, Huntington's, Alzheimer's, and motor neuron diseases. Misfolded, aggregated, or surplus proteins are efficiently degraded via distinct protein degradation pathways, including the ubiquitin-proteasome system, autophagy, and vesicular trafficking. These pathways are regulated by covalent modification of target proteins with the small protein ubiquitin and are evolutionary highly conserved from humans to yeast. The yeast Saccharomyces cerevisiae is an established model for deciphering mechanisms of protein degradation, and for the elucidation of pathways underlying programmed cell death. The expression of human neurotoxic proteins triggers cell death in yeast, with neurotoxic protein-specific differences. Therefore, yeast cell death models are suitable for analyzing the role of protein degradation pathways in modulating cell death upon expression of disease-causing proteins. This review summarizes which protein degradation pathways are affected in these yeast models, and how they are involved in the execution of cell death. I will discuss to which extent this mimics the situation in other neurotoxic models, and how this may contribute to a better understanding of human disorders.

Phosphorylation of the 19S regulatory particle ATPase subunit, Rpt6, modifies susceptibility to proteotoxic stress and protein aggregation

“…cerevisiae has been successfully utilized as a model organism to explore aging research. Indeed, studies analyzing human protein orthologs, or expression of heterologous human disease-associated proteins have revealed the value of yeast as model to study molecular mechanisms of disease [25–29]. We confirmed that Rpt6 is phosphorylated in yeast, and that this modification is increased upon stress.…”

The role of ubiquitinated TDP-43 in amyotrophic lateral sclerosis

“…Although the tardbp gene mutation is uncommon, other gene mutations related to ALS can also lead to abnormal intracellular TDP-43 levels [29,34] . Therefore, it is necessary to analyze the clearing pathway of pathological TDP-43.…”

“…The autophagy mediated TDP-43 CTFs fragmentation is caused by the failure of the phagocytosis of membrane vesicles [26] , which suggested that autophagy also affected the transcription capacity of TDP-43 proteins. In addition, several studies have illustrated that TDP-43 concentration may increase toxicity in HeLa cells, suggesting that the autophagy system and the ubiquitin proteasome system may affect transcription of TDP-43 [34] . TDP-43 mitochondrial localization inhibitory peptide can also abolish cytoplasmic TDP-43 accumulation, restore mitochondrial function, prevent neuronal loss, and alleviate motor-coordinative and cognitive deficits in adult hemizygous TDP-43 M337V mice [35] .…”

The Neuroprotective Role of Protein Quality Control in Halting the Development of Alpha-Synuclein Pathology

“…Deubiquitination of α-syn might redirect the α-syn burden toward the ALP, which is generally recognized as a more efficient α-syn degradation pathway than the UPS ( Vogiatzi et al, 2008 ). It should be noted that α-syn ubiquitination can serve as a signal for lysosome-dependent degradation ( Tofaris et al, 2011 ; Braun, 2015 ; Alexopoulou et al, 2016 ), illustrating a complex cross-talk between post-translational modifications of α-syn and cellular degradation machineries ( Choi et al, 2012 ; Haj-Yahya et al, 2013 ; Shahpasandzadeh et al, 2014 ; Tenreiro et al, 2014 ; de Oliveira et al, 2017 ). It remains unclear which α-syn degradation pathway is favored, therefore further study is needed before a viable therapeutic strategy can be designed to enhance UPS-mediated α-syn degradation.…”