Mitochondria, Metals and Lewy bodies: Decoding Brainstem Noradrenergic Neuronal Vulnerability in Lewy Body Dementia

About the Project

Project Overview:

Lewy body dementia (LBD) syndromes—encompassing dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD)—rank as a leading neurodegenerative dementia, impacting millions worldwide with devastating cognitive and motor decline. Defined by alpha-synuclein (SYN) aggregation into Lewy bodies, these disorders strike vulnerable neurons including the locus coeruleus (LC)—a noradrenergic hub pivotal to cognition, attention, and autonomic regulation.

LC neurons endure intense metabolic demands, with binding of redox-active metals like iron and copper to neuromelanin sparking oxidative stress and protein misfolding. Mitochondrial DNA (mtDNA) instability heightens this vulnerability, potentially supercharging SYN pathology and neuronal demise—yet the LC remains underexplored versus substantia nigra dopamine cells.

This project unravels how mtDNA instability, metallome dyshomeostasis, and SYN aggregation interplay in LC neurons within LBD subtypes. We hypothesise that subtype-specific mtDNA defects, allied with Fe/Cu (and possible Zn) buildup, intensify SYN damage, yielding detectable DLB vs PDD signatures at single-cell scale. For this we will use secured post-mortem brain tissues from individuals with DLB or PDD, compared to controls.

We will use two parallel pipelines. Firstly, individual neuromelanin/noradrenergic neurons will be isolated, mtDNA will be amplified using long-range PCR, and mtDNA rearrangements will be mapped using Nanopore long-read sequencing and bioinformatics. Secondly, the metallome will be studied using synchrotron XRF/XAS—high-res mapping and speciation, in SYN+ vs SYN− cells and to contrast DLB and PDD.

Training and Skills:

The project offers an opportunity to master a range of neuropathology techniques (anatomical mapping, histological/immunohistochemical staining of vulnerable neurons), laser capture microdissection for single-cell isolation under microscopy, and molecular workflows: long-range PCR, electrophoresis, qPCR, Oxford Nanopore library prep/long-read sequencing for mtDNA variants/rearrangements.

You can also dive into bioinformatics, and learn heteroplasmy filtering, deletion/duplication calling, breakpoint validation, statistics, and the reproducible use of pipelines, plus synchrotron sample prep and imaging for studying the metallome. The work takes place between three different labs with complementary expertise: Dr. Nicholls (mtDNA replication/deletions), Dr. Elson (clonal expansion/single-cell genetics), and Dr. Pienaar (LBD LC pathology/metal-mito links).

Why Newcastle?

The Newcastle Mitochondrial Research Group (MRG) are pioneers at bridging fundamental mitochondrial biology to clinical practice, collaborating with clinicians and patients to translate discoveries into therapies enhancing quality of life for mitochondrial dysfunction cases.

Funding

Students who have, or are expecting to attain, at least an upper second-class honours degree (or equivalent) in a relevant subject, are invited to apply. Funding is available for Home (UK) students to cover tuition fees, a tax-free stipend at the UKRI rate (indicative amount in year 1 in 2026-27, £21,805) and research costs, for four years. Applicants normally required to cover International fees will have to cover the difference between the Home and the International tuition fee rates. There is no additional funding available to cover NHS Immigration Health Surcharge (IHS) costs, visa costs, flights etc.

Funding for this studentship is awarded on a competitive basis and is not guaranteed; availability will depend on the outcome of the selection process and subject to final approval by the University.

HOW TO APPLY

Please complete the following application form – Google Form

Applicants can only apply for 1 project; any additional applications will not be accepted.

Applicants should send the following documents to FMSstudentships@newcastle.ac.uk:

• a CV (including contact details of at least two academic (or other relevant) referees).
• a Cover letter – stating your project choice, as well as including additional information you feel is pertinent to your application.
• copies of your relevant undergraduate degree transcripts and certificates.
• a copy of your IELTS or TOEFL English language certificate (where required)
• a copy of your passport (photo page).

A GUIDE TO THE FORMAT REQUIRED FOR THE APPLICATION DOCUMENTS IS AVAILABLE

Please submit your documents in the following format only:

• each document should be submitted as a separate attachment and should be named as follows: candidate surname, candidate name – document type. For example: Jones, Jamie – CV; Jones, Jamie – cover letter.
• Please submit .pdf documents where possible for your CV, cover letter, transcripts and certificates. Do not submit photos of certificates.
• Do not combine documents into one pdf. You may zip separate documents into a zip file to send via email if required.
• When emailing your application, please use the email subject header: FMS PhD Application 2026

Applications not meeting these criteria may be rejected.

Informal enquiries may be made to the lead supervisor of the project you are interested in.

The deadline for all applications is 12 noon BST (UK time) on Wednesday 20th May 2026.