This is a paper from London and here the tissue samples are from Tissue Bank. It is supporting the fact that the main problem in PD is in the mitochondrion, supporting the paper by González-Rodríguez P et al, Nature Nov 2021 telling the role of Compex I of Mitochondrion in PD. So this paper is somehow a bit late but still very valuable paper. The main thing is: "Critically, we show that this (mitochondrion) dysfunction occurs prior to, or concomitantly with, the earliest stages of alpha-synuclein aggregation, and certainly prior to neuronal loss, implicating mitochondrial dysfunction as an early driver of the disease, and not just an end-stage phenomenon".

When Stamler was asked about any mitochondrion studies with ATH434 he said that (if I remember this right) ATH is focusing on how ATH434 helps in eliminating iron from the cell. It is a fair point, IMO. because ATH is not in the business of basic research but in helping the mitochondrion to get rid of accumulating iron blocking ATP synthesis ( see once again the paper by Prasuhn et al in March 2022 : Relationship between brain iron deposition and mitochondrial dysfunction in idiopathic Parkinson's disease). IMO, we need this Prasuhn paper to connect iron overload to both this Toomey et al and Gonzalez-Rodriguez paper and with all of these we are very close the goal. Only the phase 2 results missing, IMO.

Acta Neuropathol Commun

. 2022 Sep 8;10(1):134.

doi: 10.1186/s40478-022-01424-6.

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

Christina E Toomey ^{# 1 2 3}, Wendy E Heywood ^{# 4}, James R Evans ^{5 6}, Joanne Lachica ^{7 5}, Sarah N Pressey ⁷, Sandrine C Foti ^{7 8}, Mesfer Al Shahrani ^{9 10}, Karishma D'Sa ^{5 6}, Iain P Hargreaves ⁹, Simon Heales ⁹, Michael Orford ⁹, Claire Troakes ¹¹, Johannes Attems ¹², Ellen Gelpi ^{13 14}, Miklos Palkovits ¹⁵, Tammaryn Lashley ^{7 8}, Steve M Gentleman ¹⁶, Tamas Revesz ^{7 8}, Kevin Mills ^{# 4}, Sonia Gandhi ^{# 17 18}

Affiliations expand

• PMID: 36076304

DOI: 10.1186/s40478-022-01424-6

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.