The deposition of intracellular protein aggregates is a common hallmark of most neurodegenerative disorders including Huntington’s disease (HD). The accepted dogma is that these aggregates lead to sequestration and impairment of components of the main intracellular protein degradation machinery, the ubiquitin-proteasome system (UPS), with fatal consequences. Our data question this dogma as we have shown that proteasomes are not sequestered into mutant huntingtin (mHTT) aggregates and remain active. Proteasomes are also able to degrade mHTT entirely when mHtt is properly ubiquitinated for degradation, and in vitro experiments show that proteasome activity towards mHtt can be improved (manuscript in preparation)

Intriguingly, the efficiencies to degrade mHTT is especially poor in neuronal cells when compared to other cell types that express mHTT proteins at the same level, which may be related to different efficiencies in the ubiquitination, recognition, unfolding and degradation of mHTT. Our preliminary data indicate that proteasomal activities change during HD progression in different brain regions, with differences in complex formation between proteasomes in highly affected areas and less affected areas of the same brain. As the less affected brain areas express mHTT at the same level, this suggests that proteasome activity can be modulated to improve clearance of mHTT and/or general protein homeostasis. Our aims are to study

1. What are the changes in proteasome complex formation and activity during HD development?
2. What is the role of proteasome-associating proteases in mHtt degradation?
3. What drives the observed changes in the observed proteasome complex formation? 
4. What are the consequences of these changes on protein substrate degradation?

Our long-term aim is to improve the recognition and degradation of mHTT, and the immediate objective of this project is to elucidate the molecular mechanism(s) underlying the changes in proteasome complex formation and improve recognition and degradation of mHTT by the proteasome and interacting enzymes.

The PhD student should have studied BioMedical Sciences or a related study with experience in biochemistry.

We offer a salary conforming to the Collective Labor Agreement for University Medical Centers in the Netherlands (CAO UMC) with a range of added fringe benefits, such as an annual bonus of 8.3%, holiday allowance, collective discounted rates for a number of insurances, an attractive bicycle scheme and/or public transport allowance, and free parking. You will be employed by the AMC Medical Research BV.

PhD students (Onderzoeker in Opleiding) are placed in scale 21, with a fulltime gross salary that ranges from € 2.279,- to € 2919,- and is based on qualifications and experience.

Starting date is ideally September 2018 for a period of 4 years.

AMC Medical Research

The AMC is more than just a hospital. It is a world in which patient care, research and education are integrated, and in which people are always central. It is an academic world full of possibilities for talented individuals that are looking for a place where they can excel. Thinking big, daring to dream, cooperating internationally. And never letting yourself be put off by ‘It’s not possible’ or ’It won’t work anyway’. That is the AMC mentality.

http://www.amc.nl/

The research groep is embedded within the department of Medical Biology at the AMC, and collaborating with various national and international groups working on the ubiquitin-proteasome system and Huntington’s Disease. 

The research group is working on the role of the ubiquitin-proteasome system in Huntington’s Disease, as described on the website https://www.medischebiologie.nl/reits-group/. We use various microscopy, biochemistry and proteomic approaches to visualise and manipulate mHtt ubiquitination and degradation in neuronal cells. Currently the group is composed of 4 postdocs, 3 technicians, 1 student and the PI. Main focus is on identifying (de)ubiquitinating enzymes involved in mHtt ubiquitination, improving proteasomal functioning towards mHtt, and small molecule compounds screens that improve mHtt clearance. The work is mainly being financed by the Dutch Huntington campaigning team (www.doodgezwegen.nl) and Cure Huntington’s Disease Initiative (CHDI)

You will work in a research team working on Htt ubiquitination and degradation, using biochemistry, proteomics and microscopy, and will be working with a postdoc and technician on this project