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Understanding molecular mechanisms of age-related neurodegenerative diseases to generate novel molecular therapies

Human dopaminergic neurons grown from stem cells derived from a patient with Parkinson's disease
Human dopaminergic neurons grown from stem cells derived from a patient with Parkinson's disease

Neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease, are set to become a "silent epidemic" placing a major healthcare burden on countries with aging populations. Our Laboratory of Molecular Neurodegeneration is focused on better understanding the molecular and genetic mechanisms of diseases using stem cell-derived neuronal cultures and novel transgenic rodent models. Our work is highly collaborative and multidisciplinary working with colleagues on the South Parks Road site and clinicians at the Oxford Hospitals. 

Our work sets out to better understand the molecular mechanisms of age-related neurodegenerative diseases with a view towards generating novel molecular therapies. We work with stem-cell derived neuronal models from patients; we are characterising novel rodent transgenic models carrying mutant or wild-type variants of disease genes; and we develop potential small molecule and genetic therapies for disease treatment.

OPDCParkinson's disease 

Richard Wade-Martins heads the Oxford Parkinson's Disease Centre (OPDC;, a major multi-disciplinary translational study funded by the Monument Trust Discovery Award from Parkinson's UK founded in 2010. The aim of the OPDC is to understand the very earliest pathways to pathology, focusing on alterations in neuronal function before cell death with a view to develop neuroprotective therapies. Our own laboratory leads on the differentiation of patient-derived induced pluripotent stem cell (iPSC) lines into dopaminergic neurons and on detailed phenotyping studies to compare neurons from Parkinson's patients with those from controls. We are also generating and characterising novel transgenic rodent models carrying wild-type or mutant forms of the genes alpha-synuclein (SNCA), leucine rich repeat kinase 2 (LRRK2) and glucocerebrosidease (GBA). Melanie Witt is the OPDC Administrator.

      ARUK-RNC-MBP-Thames-Valley.png  Alzheimer's disease

The existence of the two key molecular pathological features of Alzheimer's disease, extracellular amyloid plaques and intracellular tau tangles is well-known, but whether and how these pathologies interact is less well-understood. Our work uses iPSC lines and transgenic mouse lines engineered to express mutant disease-associated variants of the human microtubule associated protein tau (MAPT) gene. Our previous work has used the MAPT gene locus to address a central question in molecular genetics: how does non-coding genetic variation affect gene expression and splicing, leading to susceptibility to disease.

Our laboratory heads the Thames Valley Alzheimer's Research UK Network in which we are the lead molecular biology laboratory. Richard Wade-Martins is the Academic Co-Ordinator, and Lorraine Dyson is the ARUK Network Administrator.

Motor neuron disease

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating related diseases without any effective treatment. The recent discovery that an expanded GGGGCC hexanucleotide repeat in the first intron of the gene C9ORF72 causes a large proportion of both diseases has had a major impact on our thinking about diseases causes and potential therapies. Our work uses novel cellular and transgenic mouse models to address potential mechanisms by which the intronic expansions in C9ORF72 cause disease, either through a gain or loss of function, and to develop novel therapeutic targets. Other genetic causes of ALS and FTD which we study are mutations in the genes TDP-43 and FUS. Although mutations in these two genes are very rare, they form the basis for disease models and provide much information on the molecular causes of cellular dysfunction, which we have recently reviewed (Thomas et al, 2013).

Friedreich's ataxia

Friedreich’s ataxia (FRDA) is the most common inherited recessive ataxia and is caused by large GAA expansions in intron 1 of the frataxin gene (FXN). GAA expansions result in reduced FXN expression, although the mechanism of repression is not fully understood. Our work seeks to better understand the mechanisms by which the GAA intronic mutations leads to gene repression and to develop small molecule therapies to alleviate the effects of the repeat expansion. We have recently developed the first GAA-expanded FXN genomic DNA reporter model of FRDA and screened a library of novel small molecules to identify compounds which elevate mutant FRDA expression (Lufino et al, 2013).

Patient stem-cell models

We are part of the StemBANCC consortium (, a major European Union Innovative Medicines Initiative (EU IMI) program started in 2012 to characterise 1500 induced pluripotent stem cell (iPSC) lines derived from patients with important diseases of our time, including Parkinson's and Alzheimer's.

Our team

Inside the Wade-Martins Lab

Selected publications

Oxford ARUK Network Centre

Oxford ARUK Public Open Days

Annual public event on dementia research and related work taking place in Oxford

Alzheimer's Research UK Annual Conference

Annual Alzheimer's Research UK Scientific Conference to be held in Manchester in 2016

In the news

Wade-Martins lab develops new method to look for Parkinson's biomarkers

The OPDC aims to understand the earliest events that lead to Parkinson’s. As part of this research researchers in the Wade-Martins lab have made exciting discoveries about the role of alpha-synuclein oligomers in Parkinson’s in a study of post-mortem brain tissue from people with Parkinson’s and healthy controls.

OPDC recieves £6M new funding from Parkinson's UK

OPDC is celebrating after Parkinson’s UK awarded £6M to the cutting-edge research programme led by Richard Wade-Martins and Michele Hu. "In the last five years we’ve made remarkable progress. We’ve built a study integrating work in the clinic and the laboratory like nowhere else in the world. Alongside this, our program to change cells from patients’ skin into brain cells using cutting-edge stem cell technology has allowed us to gain completely new insights about Parkinson’s and how it develops. We’re delighted the new funding from Parkinson’s UK will secure the future of this and other vital projects.” OPDC lead researcher, Richard-Wade Martins

New paper from Wade-Martins lab on Friedreich's Ataxia

Expanded GAA repeats impair FXN gene expression and reposition the FXN locus to the nuclear lamina in single cells


Caution when looking at cell recycling in Parkinson’s

Our Researchers at the Oxford Parkinson’s Disease Centre have shown that cell recycling in Parkinson’s may play a more complex role than previously thought.

Research Spotlight: ‘I want to get high enough up the chain to pull others over the wall with me’

Continuing their series celebrating ‘amazing people at Oxford who you should know about’, Central University's Science Blog talks to Dayne Beccano-Kelly, an electrophysiologist and Career Development Fellow in our department and part of the Oxford Parkinson’s Disease Centre.

NIH-OxCam: a graduate student's journey to Oxford

Stewart Humble came to the Wade-Martins Lab at DPAG from Louisiana State University Health Sciences Center in New Orleans during Michaelmas Term in October 2016 as part of the National Institutes of Health Oxford-Cambridge Scholars Programme (NIH-OxCam), an accelerated, individualised doctoral training programme, to help him make the transition to a Physician-Scientist career path. This opened up the world of basic science, translational research, and international collaboration. Over the summer of 2019, Stewart organised a lab symposium to encourage and inspire students from his home university to consider the opportunities available to them. This is the story of his journey to Oxford and what he has discovered here.

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