@article{795e35be4dd247fabc285be2cadad4ed,
title = "Mitochondrial dysfunction is a key pathological driver of early stage Parkinson's",
abstract = "BACKGROUND: The molecular drivers of early sporadic Parkinson's disease (PD) remain unclear, and the presence of widespread end stage pathology in late disease masks the distinction between primary or causal disease-specific events and late secondary consequences in stressed or dying cells. However, early and mid-stage Parkinson's brains (Braak stages 3 and 4) exhibit alpha-synuclein inclusions and neuronal loss along a regional gradient of severity, from unaffected-mild-moderate-severe. Here, we exploited this spatial pathological gradient to investigate the molecular drivers of sporadic PD. METHODS: We combined high precision tissue sampling with unbiased large-scale profiling of protein expression across 9 brain regions in Braak stage 3 and 4 PD brains, and controls, and verified these results using targeted proteomic and functional analyses. RESULTS: We demonstrate that the spatio-temporal pathology gradient in early-mid PD brains is mirrored by a biochemical gradient of a changing proteome. Importantly, we identify two key events that occur early in the disease, prior to the occurrence of alpha-synuclein inclusions and neuronal loss: (i) a metabolic switch in the utilisation of energy substrates and energy production in the brain, and (ii) perturbation of the mitochondrial redox state. These changes may contribute to the regional vulnerability of developing alpha-synuclein pathology. Later in the disease, mitochondrial function is affected more severely, whilst mitochondrial metabolism, fatty acid oxidation, and mitochondrial respiration are affected across all brain regions. CONCLUSIONS: Our study provides an in-depth regional profile of the proteome at different stages of PD, and highlights that mitochondrial dysfunction is detectable prior to neuronal loss, and alpha-synuclein fibril deposition, suggesting that mitochondrial dysfunction is one of the key drivers of early disease.",
keywords = "Brain, Mitochondria, Neurodegeneration, Parkinson{\textquoteright}s, Progression, Proteomics",
author = "Toomey, {Christina E.} and Heywood, {Wendy E.} and Evans, {James R.} and Joanne Lachica and Pressey, {Sarah N.} and Foti, {Sandrine C.} and {Al Shahrani}, Mesfer and Karishma D'Sa and Hargreaves, {Iain P.} and Simon Heales and Michael Orford and Claire Troakes and Johannes Attems and Ellen Gelpi and Miklos Palkovits and Tammaryn Lashley and Gentleman, {Steve M.} and Tamas Revesz and Kevin Mills and Sonia Gandhi",
note = "Funding Information: The study, CT and SP were funded by Parkinson{\textquoteright}s UK. SG was supported by Wellcome (100172/Z/12/2), and is an MRC Senior Clinical Fellow (MR/T008199/1). TR is partly supported by the National Institute for Health Research (NIHR) Queen Square Biomedical Research Unit in Dementia based at University College London Hospitals (UCLH), University College London (UCL). WH and KM conduct research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health which is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre. The work was undertaken at Queen Square Brain Bank for Neurological disorders. We are grateful for the help and guidance from Prof Janice Holton. Tissue was collected from: the Parkinson{\textquoteright}s UK Brain Bank at Imperial College London (Registered charity in England and Wales (258197) and in Scotland (SC037554); Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology & Neuroscience, King's College London; Newcastle Brain Tissue Resource, Institute of Neuroscience and Newcastle University Institute for Ageing; Neurological Tissue bank, University of Barcelona; Human Brain Tissue Bank, Budapest, Semmelweis University; and Netherlands Brain Bank, Amsterdam. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Funding Information: The study, CT and SP were funded by Parkinson{\textquoteright}s UK. SG was supported by Wellcome (100172/Z/12/2), and is an MRC Senior Clinical Fellow (MR/T008199/1). TR is partly supported by the National Institute for Health Research (NIHR) Queen Square Biomedical Research Unit in Dementia based at University College London Hospitals (UCLH), University College London (UCL). WH and KM conduct research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health which is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre. The work was undertaken at Queen Square Brain Bank for Neurological disorders. We are grateful for the help and guidance from Prof Janice Holton. Tissue was collected from: the Parkinson{\textquoteright}s UK Brain Bank at Imperial College London (Registered charity in England and Wales (258197) and in Scotland (SC037554); Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology & Neuroscience, King's College London; Newcastle Brain Tissue Resource, Institute of Neuroscience and Newcastle University Institute for Ageing; Neurological Tissue bank, University of Barcelona; Human Brain Tissue Bank, Budapest, Semmelweis University; and Netherlands Brain Bank, Amsterdam. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Funding Information: The research leading to these results received funding from Parkinson{\textquoteright}s UK under Grant Agreement G-1004. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = sep,
day = "8",
doi = "10.1186/s40478-022-01424-6",
language = "English",
volume = "10",
pages = "134",
journal = "Acta Neuropathologica Communications",
issn = "2051-5960",
publisher = "BioMed Central",
number = "1",
}