A Shared Metabolic Basis for Parkinson's, Alzheimer's, and Huntington's

Student thesis: Phd


Parkinson's disease (PD) is the second most common neurodegenerative disorder following Alzheimer's disease (AD). In PD, extensive loss of dopamine neurons, mainly in the substantia nigra, is found in the brain alongside proteinaceous deposits of alpha-synuclein known as Lewy bodies. Although characterised primarily by motor dysfunction, up to 80% of individuals with PD go on to develop cognitive dysfunction within 20 years of initial diagnosis, in a condition referred to as Parkinson's disease dementia (PDD). PDD shares many characteristics with other neurodegenerative diseases, such as AD and Huntington's disease (HD), including progressive dementia symptoms, neuronal loss which is initially region-specific but eventually spreads throughout the brain, and metabolic perturbations - including mitochondrial dysfunction, oxidative stress, and energy pathway disruption. Previous studies have identified specific metabolic and metallic dysregulations shared in AD and HD brains, including marked widespread increases in glucose and urea, and decreases in copper. This raised the question as to whether similar perturbations may be present in PDD. Using mass spectrometric methods, this thesis aimed to perform parallel metabolomic and metallomic analyses of PDD brain tissues, the results of which could then be compared to those obtained in AD and HD. Firstly, investigations into the effects of tissue collection variables such as post mortem delay were carried out to ascertain the suitability of different donor tissues for metallomic and metabolomic analysis. Using the results of this preliminary study, suitable tissues were selected for investigations of metals and metabolites in PDD brain tissue obtained from both the UK and the US. These investigations revealed strikingly similar findings to those observed in AD and HD, including widespread decreases in copper, increases in urea, and perturbations in metabolic pathways involved in energy production and purine metabolism, as well as regional-selective decreases in pantothenic acid. The results indicate, for the first time, a shared metabolic basis for three neurodegenerative diseases featuring dementia - raising the possibility not only of shared pathogenic mechanisms, but shared therapeutic targets for these conditions.
Date of Award31 Dec 2021
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorRichard Unwin (Supervisor), Elizabeth Cartwright (Supervisor), Nigel Hooper (Supervisor), Garth Cooper (Supervisor) & Federico Roncaroli (Supervisor)


  • Neuroscience
  • Parkinson's disease dementia
  • Mass spectrometry
  • Metabolomics
  • Multiomics
  • Huntington's disease
  • Dementia
  • Parkinson's disease
  • Alzheimer's disease
  • Essential metals

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