Toggle Main Menu Toggle Search

Open Access padlockePrints

Mitochondrial dysfunction is a key pathological driver of early stage Parkinson's

Lookup NU author(s): Professor Johannes Attems



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2022. The Author(s). 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.

Publication metadata

Author(s): Toomey CE, Heywood WE, Evans JR, Lachica J, Pressey SN, Foti SC, Al Shahrani M, D'Sa K, Hargreaves IP, Heales S, Orford M, Troakes C, Attems J, Gelpi E, Palkovits M, Lashley T, Gentleman SM, Revesz T, Mills K, Gandhi S

Publication type: Article

Publication status: Published

Journal: Acta Neuropathologica Communications

Year: 2022

Volume: 10

Issue: 1

Online publication date: 08/09/2022

Acceptance date: 09/08/2022

Date deposited: 20/09/2022

ISSN (electronic): 2051-5960

Publisher: BioMed Central Ltd


DOI: 10.1186/s40478-022-01424-6

PubMed id: 36076304


Altmetrics provided by Altmetric


Funder referenceFunder name