Mitochondria interaction networks show altered topological patterns in Parkinson’s disease

Abstract

Mitochondrial dysfunction is linked to pathogenesis of Parkinson’s disease (PD). However, individual mitochondria-based analyses do not show a uniform feature in PD patients. Since mitochondria interact with each other, we hypothesize that PD-related features might exist in topological patterns of mitochondria interaction networks (MINs). Here we show that MINs formed nonclassical scale-free supernetworks in colonic ganglia both from healthy controls and PD patients; however, altered network topological patterns were observed in PD patients. These patterns were highly correlated with PD clinical scores and a machine-learning approach based on the MIN features alone accurately distinguished between patients and controls with an area-under-curve value of 0.989. The MINs of midbrain dopaminergic neurons (mDANs) derived from several genetic PD patients also displayed specific changes. CRISPR/CAS9-based genome correction of alpha-synuclein point mutations reversed the changes in MINs of mDANs. Our organelle-interaction network analysis opens another critical dimension for a deeper characterization of various complex diseases with mitochondrial dysregulation.

Mitochondrial and Clearance Impairment in p.D620N VPS35 Patient‐Derived Neurons

“…Mitochondrial morphometrics were quantified as previously described. 19 Additional data on mitochondrial network can be consulted in Zanin et al 20…”

Advancing Personalized Medicine in Common Forms of Parkinson’s Disease through Genetics: Current Therapeutics and the Future of Individualized Management

“…This unbiased and data-driven study provided a foundational resource for the PD community through a publicly available pathways browser. Pathways previously implicated by genetics and functional studies also found to be significant in this study include endocytic trafficking [ 61 , 62 ], autophagic-lysosomal function [ 51 , 63 ], mitochondrial function [ 64 , 65 ], protein aggregation [ 66 ], neuronal transmission [ 67 ], lipid metabolism [ 68 , 69 ], and certain inflammatory pathways [ 70 , 71 ] ( Figure 1 ). It has also been shown that similar pathways can be deficient in both familial and common forms of PD [ 51 , 62 ] and multiple networks can overlap or a single pathway can act alone.…”

Gene-corrected p.A30P SNCA patient-derived isogenic neurons rescue neuronal branching and function

“…Assessment of the endogenous p.A53T SNCA expression in dopaminergic neurons against their isogenic gene corrected control have identified mitochondrial dysfunction and apoptosis from increased basal levels of oxidative and nitrosative stress 55 , reductions in neurite length and complexity 53 , and impaired mitochondria dynamics 64 . Upregulation of ER stress and activation of the unfolded protein response pathway have been found neurons in a triplication of the SNCA gene dosage 63 , and we previously reported that gene-correction of the A30P mutation rescues the mitochondrial interaction network 35 .…”

“…To control for the influence of the genetic background we assessed the bioenergetic profile of neurons directly differentiated from two different iPS clones carrying the A30P mutation, which we have previously characterised 34 . Comparing these pathological neurons against neurons from an age- and gender-matched non-PD control 35 , we find that the bioenergetic profile of both clonal cell lines carrying the A30P alpha-synuclein mutation align, with mitochondrial respiration and ATP production significantly reduced compared to the control. To further investigate the loss of ATP, we assessed the mitochondrial membrane potential (MMP) of the neurons containing the A30P mutation against gene-corrected neurons, and to control for the genetic background, a gender-matched non-PD control that we have also previously characterised 32 , finding that in the pathological neurons MMP is reduced (Supp.…”

“…Another patient-derived iPS clone from this same individual has the unique identifier HIHDNDi001-A and is referred to as A30P-3 34 . An age- and gender-matched non-PD control iPS cell line, referred to as Control-1 has been previously published 35 , and a gender-matched non-PD control iPS cell line, referred to as Control-2 has been previously published 32 . The generation of single-cell gene-corrected patient-derived iPS clones from the A30P-4 iPS cell line obtained from the A30P patient has also been described 30 .…”