Wellcome Trust Centre For Mitochondrial Research

Gavin Hudson

Biography

Gavin

My first introduction to mitochondrial genetics came in 2002, when following my undergraduate degree in microbiology, I began my PhD with Prof Patrick Chinnery investigating the genomic causes of mitochondrial disease. This introduction was the catalyst, hooking me into a career investigating mitochondrial genetics in complex disease.

Over the years I became increasingly interested in the genetics of neurodegeneration, specifically the role that inherited and acquired mtDNA variation plays in developing neurodegenerative disease.

I currently both a Parkinson’s UK Senior Research Fellowship (F-1202) and was recently awarded a Newcastle University Research Fellowship (NURF) to study the effects of mtDNA variation in Parkinson’s disease.

In addition, I am also interested in the synergistic relationship between the nuclear genome (nDNA) and mtDNA and how nDNA variation can modulate mitochondrial diseases such as Leber’s hereditary optic neuropathy (LHON).


Project Details

1. Investigating the role of inherited and acquired mitochondrial DNA variation in neurodegeneration.
The aim of this research project is to investigate the role of mitochondrial DNA (mtDNA) variation in neurodegenerative diseases. Previous research shows that particular mtDNA variants (haplogroups) can protect from or increase the risk of developing PD. We will explore this by investigating the effect of inherited mtDNA variation on cellular transcriptomics in different brain regions from PD patients, comparing RNA abundance to asymptomatic controls. Phd Student – Hannah Lowes

2. The role of cell-free mtDNA in neurodegenerative disease.
mtDNA has been found to exist cell-free within human body fluids, coined circulating cell-free mtDNA (ccf-mtDNA). Ccf-mtDNA copy number has been found to be depleted in both Parkinson’s disease (PD) and Alzheimer’s disease (AD) cerebrospinal fluid (CSF), raising the hypothesis that it could be used as a biomarker for neurodegenerative disease.

This project will utilise a broad clinical spectrum including PD, AD, dementia with Lewy bodies and Multiple Sclerosis, where we will assess the function and integrity of ccf-mtDNA within the CSF to better understand how it contributes to the development and progression of neurodegeneration. Phd Student – Hannah Lowes

3. Genetic factors modulating mitochondrial copy number.
We are performing genome-wide association studies in control cohorts, using both mitochondrial and nuclear single-nucleotide polymorphism variants and mitochondrial copy number as a quantitative trait, to identify genetic factors which regulate mitochondrial copy number variability. Once we are able to understand the complex genetic interactions between mitochondrial and nuclear DNA, we will investigate the downstream, functional effects in cells to further understand the mechanisms by which neurological, metabolic and mitochondrial diseases develop and progress. Phd Student – Beccie Brennan

4. The role of mtDNA variation in dementia with Lewy bodies.
Dementia with Lewy bodies (DLB) is a progressive degenerative dementia, hallmarked by the combined loss of cholinergic (cognitive) and dopaminergic (motor) neurons in a disease which shows similarity to both Alzheimer’s disease (AD) and Parkinson’s disease (PD).Mitochondrial dysfunction, primarily manifesting as a loss of cellular energy, is already associated with a range of age-related neurodegenerative disorders including Alzheimer’s and Parkinson’s, however, the role of mitochondrial DNA (mtDNA) in DLB has yet to be investigated.

We propose that functional mtDNA variation is a major contributing factor to the risk of developing DLB, moreover we propose that DLB risk is intrinsically linked to the formation of somatic mtDNA mutations, which accumulate with age, driving a similar pathology to that seen in both AD and PD.

Sponsor/funder

2015 – 2020, Newcastle University Research Fellowship.
“The role of mitochondrial genomics and transcriptomics in neurodegenerative disease.” (Awarded 5yrs salary + £30,000).

2017 – 2018, Michael J Fox Foundation, Project Grant (13548)
“The role of cell-free mtDNA in Parkinson’s disease” (Awarded $28,698).

2012 – 2017, UK Parkinson’s disease Society, Research Fellowship (F-1202).
“Investigating the role of inherited and acquired mtDNA variation in the pathoetiology of Parkinson’s disease.” (Initially Awarded £180.084 and Extended 2015 by £69,301).

2015 – 2017, Newcastle Healthcare Charity, Research Grant.
“Does mtDNA variation affect the prevalence and progression of dementia with Lewy bodies?” (Awarded £36,325).

Collaborators

Prof Patrick Chinnery (Department of Clinical Neurosciences, Cambridge University, UK)

Prof David Burn (ICICLE-PD, Newcastle University, UK)

Dr Aldi Kraja (Charge+, Division of Statistical Genetics Washington University , US)

Dr Valerio Corelli (Department of Biomedical and Neuromotor Sciences, Bologna, IT).

Selected publications

Scopus h-index=26 and ResearchGate Score=39.49 (calculated March 2017).

Pyle A, Lowes H, Brennan R, Kurzawa-Akanbi M, Yarnall A, Burn D, Hudson G. Reduced mitochondrial DNA is not a biomarker of depression in Parkinson’s disease. Mov Disord. 2016 Oct18. doi: 10.1002/mds.26825.

Pyle A, Anugrha H, Kurzawa-Akanbi M, Yarnall A, Burn D, Hudson G. Reduced mitochondrial DNA copy number is a biomarker of Parkinson’s disease. Neurobiol Aging. 2015;38:217.e1-6

Coxhead J, Kurzawa-Akanbi M, Hussain R, Pyle A, Chinnery P, Hudson G. Somatic mtDNA variation is an important component of Parkinson’s disease. Neurobiol Aging. 2015;38:216.e7-10

Pyle A, Brennan R, Kurzawa-Akanbi M, Yarnall A, Thouin A, Mollenhauer B, Burn D, Chinnery PF, Hudson G. Reduced CSF mitochondrial DNA is a biomarker for early-stage Parkinson’s disease. Ann Neurol. 2015;78:1000-1004.

Hudson G, Uphill J, Hummerich H, Blevins J, Gambetti P, Zerr I, Collinge J, Mead S, Chinnery PF. Inherited mtDNA variations are not strong risk factors in human prion disease. Neurobiol Aging. 2015;10:2908.e1-3

Pyle A, Hudson G, Wilson IJ, Coxhead J, Smertenko T, Herbert M, Santibanez-Koref M, Chinnery PF. Extreme-Depth Re-sequencing of Mitochondrial DNA Finds No Evidence of Paternal Transmission in Humans. PLoS Genet. 2015;11(5):e1005040.

Carbutt S, Duff J, Yarnall A, Burn DJ, Hudson G. Variation in complement protein C1q is not a major contributor to cognitive impairment in Parkinson’s disease. Neurosci Lett. 2015;6;594:66-9.

Hudson G, Gomez-Duran A, Wilson IJ, Chinnery PF. Recent mitochondrial DNA mutations increase the risk of developing common late-onset human diseases. PLoS Genet. 2014;10(5):e1004369.

Hudson G, Nalls M, Evans JR, Breen DP, Winder-Rhodes S, Morrison KE, Morris HR, Williams-Gray CH, Barker RA, Singleton AB, Hardy J, Wood NE, Burn DJ, Chinnery PF. Two-stage association study and meta-analysis of mitochondrial DNA variants in Parkinson disease. Neurology. 2013;80(22):2042-8.

Hudson G, Panoutsopoulou K, Wilson I, Southam L, Rayner NW, Arden N, Birrell F, Carluke I, Carr A, Chapman K, Deloukas P, Doherty M, McCaskie A, Ollier WE, Ralston SH, Reed MR, Spector TD, Valdes AM, Wallis GA, Wilkinson JM, Zeggini E, Samuels DC, Loughlin J, Chinnery PF; arcOGEN Consortium. No evidence of an association between mitochondrial DNA variants and osteoarthritis in 7393 cases and 5122 controls. Ann Rheum Dis. 2013;72(1):136-9.

Hudson G, Sims R, Harold D, Chapman J, Hollingworth P, Gerrish A, Russo G, Hamshere M, Moskvina V, Jones N, Thomas C, Stretton A, Holmans PA, O’Donovan MC, Owen MJ, Williams J, Chinnery PF; GERAD1 Consortium. No consistent evidence for association between mtDNA variants and Alzheimer disease. Neurology. 2012;78(14):1038-42.

Contact

Gavin Hudson
Institute of Genetic Medicine
Newcastle University
International Centre for Life
Central Parkway
Newcastle upon Tyne
NE1 3BZ
UK

Email: Gavin.Hudson@ncl.ac.uk
Telephone: +44 (0) 191 241 8818