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The impact of protein ubiquitination on ageing and ageing-associated diseases

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

"Ageing is characterized by a general functional decline of cells, tissues and organs with increased risk of disease, such as neurodegenerative disorders. Maintenance of protein homeostasis is a long-term challenge not only for individual cells but also for the entire organism. Ageing and many ageing-associated disorders involve perturbed energy balance and disturbed metabolism and increasing evidence suggests that metabolic syndrome is interrelated with many age-related neurodegenerative diseases, including Parkinson’s and Alzheimer’s diseases.

In recent years it became evident that ubiquitin-dependent regulation of signalling pathways regulate numerous cellular processes and have a major impact on organismal ageing. The age-related impairment of ubiquitin-dependent proteolysis results in enhanced accumulation of damaged proteins and organelles which can lead to loss of cell integrity, tissue degeneration and can also shorten lifespan. On the other hand, direct ubiquitination of distinct lifespan regulators also actively influences the life expectancy of different organisms (1-4). Deubiquitinating enzymes (DUBs) are responsible for reversing the ubiquitination of proteins by removing ubiquitin moieties attached to the substrates. DUBs are emerging as critical regulators of the stability, activity, complex formation and intracellular localization of a wide variety of proteins. Consequently, DUBs play key regulatory roles in a multitude of processes, and their dysfunction is linked to various human diseases. Despite intensive research there is only little known about the potential function of DUBs maintenance of the ageing proteome.

The project will focus on defining the tissue specific role of DUBs in proteostasis maintenance in the organismal context of increasing metabolic stress during ageing. This research will benefit from the use of the great model organism of ageing research, C. elegans, and the well-established molecular, genetic, biochemistry and cell biology methods available in this system. The major aim is to understand how ubiquitin-dependent regulation of the proteome linked to metabolic dysfunction contributes to the pathogenesis of age-related neurodegenerative diseases and its impact on the ageing of the whole organism.

Funding Notes

Applicants should hold or expect to gain a minimum of a 2:1 Bachelor Degree or equivalent in a Biology related subject. Experience with C. elegans or with cell culture would be advantageous, but not a pre-requisite.


"1. Kevei, E. & Hoppe, T. (2014) Ubiquitin sets the timer: impacts on aging and longevity, Nature structural & molecular biology. 21, 290-2.
2. Kevei, E., Pokrzywa, W. & Hoppe, T. (2017) Repair or destruction-an intimate liaison between ubiquitin ligases and molecular chaperones in proteostasis, FEBS letters. 591, 2616-2635.
3. Tawo, R., Pokrzywa, W., Kevei, E., Akyuz, M. E., Balaji, V., Adrian, S., Hohfeld, J. & Hoppe, T. (2017) The Ubiquitin Ligase CHIP Integrates Proteostasis and Aging by Regulation of Insulin Receptor Turnover, Cell. 169, 470-482 e13.
4. Kuhlbrodt, K., Janiesch, P. C., Kevei, E., Segref, A., Barikbin, R. & Hoppe, T. (2011) The Machado-Joseph disease deubiquitylase ATX-3 couples longevity and proteostasis, Nat Cell Biol. 13, 273-81.

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