Cookies

This site requires the use of cookies as defined by our Terms and Conditions.  We have provided a detailed description of how cookies work and are used on the site.  To accept cookies, please click the "Accept Cookies" button.
View All Vacancies

PhD Studentship (4 years) - Unravelling the role of DJ-1 in cellular RNA dynamics: relevance for neurodegeneration

School of Biosciences

Location:  Aston University Main Campus
Basis:  Full Time
Closing Date:  23.59 hours GMT on Sunday 10 January 2021
Reference:  R200314
Release Date:  Tuesday 10 November 2020

Supervisor: Dr. Mariaelena Repici

Associate Supervisors: Professor Andrew Devitt, Dr. Ivana Milic

Project Reference: MIBTP_Repici_DJ-1

BBSRC Strategic Research Priority: Neuroscience and Behaviour

Applications are invited for four year Postgraduate studentships, supported by the Midlands Integrative Biosciences Training Partnership (MIBTP) and Biotechnology and Biological Sciences Research Council (BBSRC). Up to 6 studentships are available.

The studentships are available to start in October 2021. 

Financial Support

The studentships include a fee bursary to cover the Home fees rate, plus a tax free stipend of at least £15,285 p.a (to rise in line with UKRI recommendation).

Overseas Applicants

Overseas applicants may apply for this studentship, and the home fees rate will be covered. UKRI funding will not cover the difference between UK tuition fees and international tuition fees; international tuition fee payers will be required to fund the fee difference themselves. MIBTP encourages international students with existing sources of funding (e.g. fellowships) to apply. The difference between home and international fees is £13,443 in 2020/21. Please confirm in your application how you will fund the fee difference."

Background to the Studentship

All MIBTP scholars will join a programme of skills training in year 1. Applicants are required to select an area of study (Sustainable Agriculture and Food, Understanding the Rules of Life, Renewable Resources and Clean Growth or Integrated Understanding of Health) but may join the programme with or without selecting a preferred project. Part of the skills training programme includes short rotation projects and students are able to choose a PhD project once they have experienced these differing research environments.

Potential PhD projects are provided to give applicants an idea of the breadth of research within MIBTP and specific research topics at Aston University. You can browse the other projects available here. Additional projects will become available during Year 1 and students can work with potential supervisors during their first year to develop a particular project.

Project Outline

Mutations in the gene encoding DJ-1 are associated with autosomal recessive forms of Parkinson’s disease (PD). DJ-1 plays a role in protection from oxidative stress, but how it functions as an “upstream” oxidative stress sensor and whether this relates to PD is still unclear. Intriguingly, DJ-1 may act as an RNA binding protein associating with specific mRNA transcripts in the human brain. We previously reported that the yeast DJ-1 homolog Hsp31 localizes to mRNA granules known as stress granules (SGs) and P-bodies after glucose starvation, suggesting a role for DJ-1 in RNA dynamics. SGs are cytoplasmic aggregates that represent the morphological consequence of an mRNA triage process triggered by environmental stresses (Anderson and Kedersha, 2008). These structures are characterized by the presence of the translationally silent 48S preinitiation complex (mRNA transcripts, 40S ribosomal proteins, eIF3, eIF4A, eIF4B, eIF4G and eIF4E and PABP-1) and represent the physical place within the cytoplasm of stressed cells where the fate of mRNA transcripts is decided. In our recently published article in Molecular Neurobiology (Repici et al., 2019) we show that DJ-1 interacts with several SG components in mammalian cells and localizes to SGs and P-bodies upon induction of stress. Moreover, we find that subpopulations of mRNAs which interact with DJ-1 localize to SGs after stress, suggesting that DJ-1 may target specific mRNAs to mRNP granules. Notably, we demonstrate that DJ-1 associates with SGs arising from N-methyl-D-aspartate (NMDA) excitotoxicity in primary neurons and parkinsonism-related toxins in dopaminergic cell cultures. Our results indicate that DJ-1 is associated with cytoplasmic RNA granules arising during stress and neurodegeneration, providing a possible link between DJ-1 and RNA dynamics which may be relevant for PD pathogenesis and fits within the emerging area of RNA metabolism and neurodegenerative diseases.

This project aims at further investigating the role of DJ-1 in RNA dynamics, to elucidate how DJ-1 interactions with mRNAs changes in pathological versus physiological conditions. This will be achieved by a) exploring the DJ-1/RNA interactome and its role in translation, b) studying the compartmentalization of DJ-1 within stress granules and c) determining the mRNA populations targeted by DJ-1 to SGs. Ultimately, such analyses will further elucidate how DJ-1 loss of function leads to PD, providing important insight into the molecular pathogenesis of this disorder and potentially informing novel therapeutic strategies.

 The project will involve:

  • Genomic approach to study the RNA populations in neuronal cells that interact with DJ-1 in different stress conditions. The mouse dopaminergic neuronal SN4741 cell line will be exposed to hyperosmotic shock, oxidative stress or MPP+, and will be lysed in polysome lysis buffer. RNAs interacting with DJ-1 will be purified by co-immunoprecipitation as in Repici et al. 2109, and RNA sequencing will be carried out. Gene ontology and related bioinformatics approaches will be employed to identify functional groups arising from the various stimuli, which will inform the signalling pathways regulated by DJ-1.
  • Use of U-2 OS cells expressing a GFP-G3BP1 fusion protein to isolate SG cores after different type of stress (hyperosmotic shock, oxidative stress, MPP+). Immunoblotting will be performed on the SG cores to look for total DJ-1, as well as oxidized forms of DJ-1. This will clarify whether DJ-1 acts as an RNA shuttle protein in the outer shell of SGs or as a core SG component. Mass spectrometry will be used for the analysis of SG components to identify DJ-1 oxidation state and post translational modifications.
  •  RNA in situ hybridization of the DJ-1 interacting mRNAs in stress conditions will be performed using using the RNAScope Multiplex Assay and combined with immunofluorescence for SG markers in relevant cells. This work will clarify whether candidate mRNAs being regulated by DJ-1 are being sequestered in SGs during stress conditions.

References:

P. Anderson and N. Kedersha. Trends Biochem Sci 33 (3), 141 (Mar 2008).

Repici M, Hassanjani M, Maddison DC, Garção P, Cimini S, Patel B, Szegö ÉM, Straatman KR, Lilley KS, Borsello T, Outeiro TF, Panman L, Giorgini F. The Parkinson's Disease-Linked Protein DJ-1 Associates with Cytoplasmic mRNP Granules During Stress and Neurodegeneration. Mol Neurobiol. 2019 Jan;56(1):61-77.

Person Specification

The successful applicant should have been awarded, or expect to achieve, a Masters degree in a relevant subject with a 60% or higher weighted average, and/or a First or Upper Second Class Honours degree (or an equivalent qualification from an overseas institution) in a relevant subject. Full entry requirements for Aston University can be found on our website.

Evidence of quantitative training is required. For example, AS or A level Maths, IB Standard or Higher Maths, or university level maths/statistics course. Full entry requirements for MIBTP can be found on their website.

Contact information

For further information on the advertised project, please contact Dr. Mariaelena Repici at m.repici@aston.ac.uk

Submitting an application

In order to apply for the MIBTP PhD studentship you must:

  1. Check your eligibility. 
  2. Complete a PhD application form on the Aston University website. From the drop-down options select School of Life and Health Sciences; October; Full time; Postgraduate Research; “Research Biomedical Sciences October 2021 Entry (Full-time)”.
  3. Notify MIBTP of your application by completing the online notification form; ensuring that you upload a current CV to the form.
  4. Review the MIBTP Data Privacy Policy to understand how we process your personal data.


When completing the Aston University application form, you will need to ensure to include the following documents:

  • Copies of your academic qualifications for your Bachelor degree, and Masters degree (if studied); this should include both certificates and transcripts, and must be translated in to English.
  • A personal statement*
  • A copy of your current CV
  • Two academic references
  • Proof of your English Language proficiency for non-Native English speakers, further details can be found on our website

*Please note that a project proposal is not required, however your Personal Statement should address your ability & knowledge of the research area.  Where applying for a specific project, please include the supervisor name, project title and project reference in your Personal Statement. 

If you require further information about the application process please contact the Postgraduate Admissions team at pgr_admisssions@aston.ac.uk 

Email details to a friend

Further particulars and application forms are available in alternative formats on request i.e. large print, Braille, tape or CD Rom.

If you have any questions, please do not hesitate to contact HR via recruitment@aston.ac.uk


Login

Login

Forgotten Details

Register