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

Zanin, Massimiliano; Santos, Bruno F.R.; Antony, Paul; Berenguer-Escuder, Clara; Larsen, Simone B.; Hanss, Zoé; Barbuti, Peter A.; Baumuratov, Aidos; Großmann, Dajana; Capelle, Christophe; Weber, Joseph; Balling, Rudi; Ollert, Markus; Krueger, Rejko; Diederich, Nico J.; He, Feng

doi:10.1101/2020.03.09.984195

Cited by 2 publications

(3 citation statements)

References 53 publications

(57 reference statements)

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

Section: Methodsmentioning

confidence: 99%

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

et al. 2020

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A BS TRACT: Background: VPS35 is part of the retromer complex and is responsible for the trafficking and recycling of proteins implicated in autophagy and lysosomal degradation, but also takes part in the degradation of mitochondrial proteins via mitochondria-derived vesicles. The p.D620N mutation of VPS35 causes an autosomal-dominant form of Parkinson's disease (PD), clinically representing typical PD. Objective: Most of the studies on p.D620N VPS35 were performed on human tumor cell lines, rodent models overexpressing mutant VPS35, or in patient-derived fibroblasts. Here, based on identified target proteins, we investigated the implication of mutant VPS35 in autophagy, lysosomal degradation, and mitochondrial function in induced pluripotent stem cell-derived neurons from a patient harboring the p.D620N mutation. Methods: We reprogrammed fibroblasts from a PD patient carrying the p.D620N mutation in the VPS35 gene and from two healthy donors in induced pluripotent stem cells. These were subsequently differentiated into neuronal precursor cells to finally generate midbrain dopaminergic neurons. Results: We observed a decreased autophagic flux and lysosomal mass associated with an accumulation of α-synuclein in patient-derived neurons compared to controls. Moreover, patient-derived neurons presented a mitochondrial dysfunction with decreased membrane potential, impaired mitochondrial respiration, and increased production of reactive oxygen species associated with a defect in mitochondrial quality control via mitophagy. Conclusion: We describe for the first time the impact of the p.D620N VPS35 mutation on autophago-lysosome pathway and mitochondrial function in stem cell-derived neurons from an affected p.D620N carrier and define neuronal phenotypes for future pharmacological interventions.

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

Section: Methodsmentioning

confidence: 99%

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

et al. 2020

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“…Upregulation of ER stress and activation of the unfolded protein response pathway have been found neurons in a triplication of the SNCA gene dosage 54 , and we previously reported that genecorrection of the A30P mutation impairs the mitochondrial network 56 .…”

Section: Discussionmentioning

confidence: 82%

“…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 53 , reductions in neurite length and complexity 51 , and impaired mitochondria dynamics 55 . Upregulation of ER stress and activation of the unfolded protein response pathway have been found neurons in a triplication of the SNCA gene dosage 54 , and we previously reported that genecorrection of the A30P mutation impairs the mitochondrial network 56 .…”

Section: Discussionmentioning

confidence: 82%

Gene-corrected Parkinson’s disease neurons show the A30P alpha-synuclein point mutation leads to reduced neuronal branching and function

Barbuti

Santos

Antony

et al. 2020

Preprint

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Parkinson's disease is characterised by the degeneration of A9 dopaminergic neurons and the pathological accumulation of alpha-synuclein. In a patient-derived stem cell model, we have generated dopaminergic neurons from an individual harbouring the p.A30P SNCA mutation and compared those neurons against gene-corrected isogenic control cell lines. We have used confocal microscopy to assess the neuronal network, specifically segmenting dopaminergic neurons and have identified image-based phenotypes showing axonal impairment and reduced neurite branching. We show using multi-electrode array (MEA) technology that the neurons carrying the endogenous p.A30P alpha-synuclein mutation are functionally impaired and identified mitochondrial dysfunction as a pathogenic cellular phenotype. We report that against gene-corrected isogenic control cell lines the neurons carrying the p.A30P SNCA mutation have a deficit and are susceptible to the mitochondrial toxin and environmental pesticide Rotenone. Our data supports the use of isogenic cell lines in identifying image-based pathological phenotypes that can serve as an entry point for future disease modifying compound screenings and drug discovery strategies.

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

Cited by 2 publications

References 53 publications

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

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

Gene-corrected Parkinson’s disease neurons show the A30P alpha-synuclein point mutation leads to reduced neuronal branching and function

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