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.

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

10.1101/2020.03.09.984195 ◽

2020 ◽

Cited By ~ 1

Author(s):

Massimiliano Zanin ◽

Bruno F. R. Santos ◽

Paul M.A. Antony ◽

Clara Berenguer-Escuder ◽

Simone B. Larsen ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Point Mutations ◽

Alpha Synuclein ◽

Interaction Networks ◽

Scale Free ◽

Midbrain Dopaminergic Neurons ◽

Machine Learning Approach

SUMMARYMitochondrial 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-mitochondria interaction networks (MINs). Here we showed that MINs form non-classical scale-free supernetworks in colonic ganglia both from healthy controls and PD patients, however, altered topological patterns are observed in PD patients. These patterns highly correlate with PD clinical scores and a machine-learning approach based on the MIN features accurately distinguish 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 display specific changes. CRISPR/CAS9-based genome correction of alpha-synuclein point mutations reverses the changes in MINs of mDANs. Our MIN network analysis opens a new dimension for a deeper characterization of various complex diseases with mitochondrial dysregulation.

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Alpha-synuclein stepwise aggregation reveals features of an early onset mutation in Parkinson’s disease

Communications Biology ◽

10.1038/s42003-019-0598-9 ◽

2019 ◽

Vol 2 (1) ◽

Cited By ~ 15

Author(s):

Guilherme A. P. de Oliveira ◽

Jerson L. Silva

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Early Onset ◽

Point Mutations ◽

Alpha Synuclein ◽

Amyloid Formation ◽

Wild Type ◽

Cryo Electron Microscopy ◽

Familial Parkinson’S Disease ◽

Direct Detector

Abstract Amyloid formation is a process involving interconverting protein species and results in toxic oligomers and fibrils. Aggregated alpha-synuclein (αS) participates in neurodegenerative maladies, but a closer understanding of the early αS polymerization stages and polymorphism of heritable αS variants is sparse still. Here, we distinguished αS oligomer and protofibril interconversions in Thioflavin T polymerization reactions. The results support a hypothesis reconciling the nucleation-polymerization and nucleation-conversion-polymerization models to explain the dissimilar behaviors of wild-type and the A53T mutant. Cryo-electron microscopy with a direct detector shows the polymorphic nature of αS fibrils formed by heritable A30P, E46K, and A53T point mutations. By showing that A53T rapidly nucleates competent species, continuously elongates fibrils in the presence of increasing amounts of seeds, and overcomes wild-type surface requirements for growth, our findings place A53T with features that may explain the early onset of familial Parkinson’s disease cases bearing this mutation.

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Alpha-Synuclein in Parkinson’s Disease: From Pathogenetic Dysfunction to Potential Clinical Application

Parkinson s Disease ◽

10.1155/2016/1720621 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 34

Author(s):

Lingjia Xu ◽

Jiali Pu

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Current Knowledge ◽

Point Mutations ◽

Lewy Bodies ◽

Neuronal Cell ◽

Cell Loss ◽

Alpha Synuclein ◽

Substantia Nigra Pars Compacta ◽

Lewy Neurites

Parkinson’s disease is a neurodegenerative disease/synucleinopathy that develops slowly; however, there is no efficient method of early diagnosis, nor is there a cure. Progressive dopaminergic neuronal cell loss in the substantia nigra pars compacta and widespread aggregation of theα-synuclein protein (encoded by theSNCAgene) in the form of Lewy bodies and Lewy neurites are the neuropathological hallmarks of Parkinson’s disease. TheSNCAgene has undergone gene duplications, triplications, and point mutations. However, the specific mechanism ofα-synuclein in Parkinson’s disease remains obscure. Recent research showed that variousα-synuclein oligomers, pathological aggregation, and propagation appear to be harmful in certain areas in Parkinson’s disease patients. This review summarizes our current knowledge of the pathogenetic dysfunction ofα-synuclein associated with Parkinson’s disease and highlights current approaches that seek to develop this protein as a possible diagnostic biomarker and therapeutic target.

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The Convergence of Alpha-Synuclein, Mitochondrial, and Lysosomal Pathways in Vulnerability of Midbrain Dopaminergic Neurons in Parkinson’s Disease

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.580634 ◽

2020 ◽

Vol 8 ◽

Author(s):

Georgia Minakaki ◽

Dimitri Krainc ◽

Lena F. Burbulla

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Alpha Synuclein ◽

Motor Symptoms ◽

Intracellular Iron ◽

Therapeutic Benefits ◽

Midbrain Dopaminergic Neurons ◽

Midbrain Dopamine ◽

Key Events

Parkinson’s disease (PD) is the second most common neurodegenerative disease, characterized by progressive bradykinesia, rigidity, resting tremor, and gait impairment, as well as a spectrum of non-motor symptoms including autonomic and cognitive dysfunction. The cardinal motor symptoms of PD stem from the loss of substantia nigra (SN) dopaminergic (DAergic) neurons, and it remains unclear why SN DAergic neurons are preferentially lost in PD. However, recent identification of several genetic PD forms suggests that mitochondrial and lysosomal dysfunctions play important roles in the degeneration of midbrain dopamine (DA) neurons. In this review, we discuss the interplay of cell-autonomous mechanisms linked to DAergic neuron vulnerability and alpha-synuclein homeostasis. Emerging studies highlight a deleterious feedback cycle, with oxidative stress, altered DA metabolism, dysfunctional lysosomes, and pathological alpha-synuclein species representing key events in the pathogenesis of PD. We also discuss the interactions of alpha-synuclein with toxic DA metabolites, as well as the biochemical links between intracellular iron, calcium, and alpha-synuclein accumulation. We suggest that targeting multiple pathways, rather than individual processes, will be important for developing disease-modifying therapies. In this context, we focus on current translational efforts specifically targeting lysosomal function, as well as oxidative stress via calcium and iron modulation. These efforts could have therapeutic benefits for the broader population of sporadic PD and related synucleinopathies.

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