Understanding molecular mechanisms of age-related neurodegenerative diseases to generate novel molecular therapies
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.
Richard Wade-Martins heads the Oxford Parkinson's Disease Centre (OPDC; www.opdc.ox.ac.uk), 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). Lorraine Dyson is the OPDC Administrator.
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 on the Network Committee, 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 (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 (www.stembancc.org), 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.
Oxford Parkinson's Disease Centre
The Oxford Parkinson's Disease Centre (OPDC; www.opdc.ox.ac.uk) is a leading interdisciplinary research centre launched in February 2010 following the award of the Monument Trust Discovery Award from Parkinson's UK.
Exploiting the unique interdisciplinary research environment within Oxford, the centre focuses on understanding the earliest pathological pathways in PD. Internationally-recognised scientists with strengths in genetics and genomics, transgenic rodent models, in vivo neuroanatomy and neuropharmacology of the basal ganglia, magnetic resonance imaging (MRI), and analysis of protein biomarkers, are working closely with experts in epidemiology and clinical neurology to better understand the causes of PD.
Oxford ARUK Network Centre
EU EFACTS Consortium
The European Friedreich’s Ataxia Consortium for Translational Studies (EU EFACTS) assembles a body of expertise to adopt a translational research strategy for the rare autosomal recessive neurological disease, Friedreich’s ataxia (FRDA). Find out more about EFACTS.
FORMA Therapeutics, the OPDC, and the Alzheimer’s Research UK Oxford Drug Discovery Institute (ODDI) at Oxford University have entered into a collaboration and license agreement to identify, validate and develop deubiquitinating enzyme (DUB) inhibitors for the treatment of neurodegenerative diseases.
The FORMA/Oxford collaboration brings together world class expertise in disease molecular pathology and DUB biology from University teams, including the Alzheimer’s Research UK Oxford Drug Discovery Institute (ODDI) and the Oxford Parkinson’s Disease Centre (OPDC), and FORMA’s deep expertise in small molecule drug design and development.
Dementias Platform UK
The MRC Dementias Platform UK (DPUK) is a multi-million pound public-private partnership, developed and led by the Medical Research Council, to accelerate progress in, and open up, dementias research. The DPUK’s aims are early detection, improved treatment and ultimately, prevention, of dementias.
Richard Wade-Martins will play a key role in the Stem Cell Network within DPUK which will comprise co-ordinated programmes for the immortalisation of selected cell lines, high-throughput genome editing, and detailed cell phenotyping.
GABA uptake transporters support dopamine release in dorsal striatum with maladaptive downregulation in a parkinsonism model.
Roberts BM. et al, (2020), Nat Commun, 11
CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson's disease.
Bengoa-Vergniory N. et al, (2020), Nat Commun, 11
USP30 sets a trigger threshold for PINK1-PARKIN amplification of mitochondrial ubiquitylation.
Rusilowicz-Jones EV. et al, (2020), Life Sci Alliance, 3
Cohort Profile: the Oxford Parkinson's Disease Centre Discovery Cohort Magnetic Resonance Imaging sub-study (OPDC-MRI)
GRIFFANTI L. et al, (2020), BMJ Open
In the news
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 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
16 October 2020
New Future Leaders Fellow Dr Beccano-Kelly will lead research into synaptic health over time in neurodegeneration.
28 September 2020
A collaborative study led by the OPDC's Dr Nora Bengoa-Vergniory has shown that compounds known as molecular tweezers could become a promising disease modifying therapy for Parkinson’s.
22 September 2020
The World Parkinson Coalition has brought in eight new Science Ambassadors to increase outreach to researchers ahead of their next major Congress.
25 August 2020
New results from a collaborative Oxford Parkinson’s Disease Centre and Cardiff University study on the cellular origins of Parkinson's could be key to developing new treatments.