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Mitochondria, parkinson's disease

Daniel Little, Christin Luft, Olukunbi Mosaku, Maëlle Lorvellec, Zhi Yao, Sébastien Paillusson, Janos Kriston-Vizi, Sonia Gandhi, Andrey Y Abramov, Robin Ketteler, Michael J Devine, Paul Gissen
Mitochondrial dysfunction is implicated in many neurodegenerative diseases including Parkinson's disease (PD). Induced pluripotent stem cells (iPSCs) provide a unique cell model for studying neurological diseases. We have established a high-content assay that can simultaneously measure mitochondrial function, morphology and cell viability in iPSC-derived dopaminergic neurons. iPSCs from PD patients with mutations in SNCA and unaffected controls were differentiated into dopaminergic neurons, seeded in 384-well plates and stained with the mitochondrial membrane potential dependent dye TMRM, alongside Hoechst-33342 and Calcein-AM...
June 13, 2018: Scientific Reports
Jialong Chen, Yixian Ren, Chen Gui, Menglan Zhao, Xian Wu, Kanmin Mao, Wenjun Li, Fei Zou
α-synuclein abnormal accumulation and mitochondria dysfunction are involved in the pathogenesis of Parkinson's disease. Selective autophagy of mitochondria (mitophagy) is a crucial component of the network controlling the mitochondrial homeostasis. However, the underlying mechanism that mutant α-synuclein induces mitochondrial abnormality through mitophagy impairment is not fully understood. Here, we showed that mutant A53T α-synuclein accumulation impaired mitochondrial function and Parkin-mediated mitophgy in α-synucleinA53T model...
June 13, 2018: Cell Death & Disease
Raffaele Ferrari, Demis A Kia, James E Tomkins, John Hardy, Nicholas W Wood, Ruth C Lovering, Patrick A Lewis, Claudia Manzoni
BACKGROUND: Genome wide association studies (GWAS) have helped identify large numbers of genetic loci that significantly associate with increased risk of developing diseases. However, translating genetic knowledge into understanding of the molecular mechanisms underpinning disease (i.e. disease-specific impacted biological processes) has to date proved to be a major challenge. This is primarily due to difficulties in confidently defining candidate genes at GWAS-risk loci. The goal of this study was to better characterize candidate genes within GWAS loci using a protein interactome based approach and with Parkinson's disease (PD) data as a test case...
June 13, 2018: BMC Genomics
Marthe H R Ludtmann, Plamena R Angelova, Mathew H Horrocks, Minee L Choi, Margarida Rodrigues, Artyom Y Baev, Alexey V Berezhnov, Zhi Yao, Daniel Little, Blerida Banushi, Afnan Saleh Al-Menhali, Rohan T Ranasinghe, Daniel R Whiten, Ratsuda Yapom, Karamjit Singh Dolt, Michael J Devine, Paul Gissen, Tilo Kunath, Morana Jaganjac, Evgeny V Pavlov, David Klenerman, Andrey Y Abramov, Sonia Gandhi
Protein aggregation causes α-synuclein to switch from its physiological role to a pathological toxic gain of function. Under physiological conditions, monomeric α-synuclein improves ATP synthase efficiency. Here, we report that aggregation of monomers generates beta sheet-rich oligomers that localise to the mitochondria in close proximity to several mitochondrial proteins including ATP synthase. Oligomeric α-synuclein impairs complex I-dependent respiration. Oligomers induce selective oxidation of the ATP synthase beta subunit and mitochondrial lipid peroxidation...
June 12, 2018: Nature Communications
Florian A Britto, Fabienne Cortade, Yassine Belloum, Marine Blaquière, Yann S Gallot, Aurélie Docquier, Allan F Pagano, Elodie Jublanc, Nadia Bendridi, Christelle Koechlin-Ramonatxo, Béatrice Chabi, Marc Francaux, François Casas, Damien Freyssenet, Jennifer Rieusset, Sophie Giorgetti-Peraldi, Gilles Carnac, Vincent Ollendorff, François B Favier
BACKGROUND: Skeletal muscle atrophy is a common feature of numerous chronic pathologies and is correlated with patient mortality. The REDD1 protein is currently recognized as a negative regulator of muscle mass through inhibition of the Akt/mTORC1 signaling pathway. REDD1 expression is notably induced following glucocorticoid secretion, which is a component of energy stress responses. RESULTS: Unexpectedly, we show here that REDD1 instead limits muscle loss during energetic stresses such as hypoxia and fasting by reducing glycogen depletion and AMPK activation...
June 12, 2018: BMC Biology
Alpana Singh, Lianteng Zhi, Hui Zhang
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene account for most common causes of familial and sporadic Parkinson's disease (PD) and are one of the strongest genetic risk factors in sporadic PD. Pathways implicated in LRRK2-dependent neurodegeneration include cytoskeletal dynamics, vesicular trafficking, autophagy, mitochondria, and calcium homeostasis. However, the exact molecular mechanisms still need to be elucidated. Both genetic and environmental causes of PD have highlighted the importance of mitochondrial dysfunction in the pathogenesis of PD...
June 9, 2018: Brain Research
Marc P M Soutar, Liam Kempthorne, Shuichi Miyakawa, Emily Annuario, Daniela Melandri, Jasmine Harley, Gregory A O'Sullivan, Selina Wray, David C Hancock, Mark R Cookson, Julian Downward, Mark Carlton, Hélène Plun-Favreau
The discovery of mutations within genes associated with autosomal recessive Parkinson's disease allowed for the identification of PINK1/Parkin regulated mitophagy as an important pathway for the removal of damaged mitochondria. While recent studies suggest that AKT-dependent signalling regulates Parkin recruitment to depolarised mitochondria, little is known as to whether this can also regulate PINK1 mitochondrial accumulation and downstream mitophagy. Here, we demonstrate that inhibition of AKT signalling decreases endogenous PINK1 accumulation in response to mitochondria depolarisation, subsequent Parkin recruitment, phosphorylation of ubiquitin, and ultimately mitophagy...
June 11, 2018: Scientific Reports
Jorge S Valadas, Giovanni Esposito, Dirk Vandekerkhove, Katarzyna Miskiewicz, Liesbeth Deaulmerie, Susanna Raitano, Philip Seibler, Christine Klein, Patrik Verstreken
Parkinson's disease patients report disturbed sleep patterns long before motor dysfunction. Here, in parkin and pink1 models, we identify circadian rhythm and sleep pattern defects and map these to specific neuropeptidergic neurons in fly models and in hypothalamic neurons differentiated from patient induced pluripotent stem cells (iPSCs). Parkin and Pink1 control the clearance of mitochondria by protein ubiquitination. Although we do not observe major defects in mitochondria of mutant neuropeptidergic neurons, we do find an excess of endoplasmic reticulum-mitochondrial contacts...
June 1, 2018: Neuron
Diana Luz Juárez-Flores, Ingrid González-Casacuberta, Mario Ezquerra, María Bañó, Francesc Carmona-Pontaque, Marc Catalán-García, Mariona Guitart-Mampel, Juan José Rivero, Ester Tobias, Jose Cesar Milisenda, Eduard Tolosa, Maria Jose Marti, Ruben Fernández-Santiago, Francesc Cardellach, Constanza Morén, Glòria Garrabou
BACKGROUND: Mutations in leucine rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD). Mitochondrial and autophagic dysfunction has been described as etiologic factors in different experimental models of PD. We aimed to study the role of mitochondria and autophagy in LRRK2 G2019S -mutation, and its relationship with the presence of PD-symptoms. METHODS: Fibroblasts from six non-manifesting LRRK2 G2019S -carriers (NM-LRRK2 G2019S ) and seven patients with LRRK2 G2019S -associated PD (PD-LRRK2 G2019S ) were compared to eight healthy controls (C)...
June 8, 2018: Journal of Translational Medicine
Sandra Franco-Iborra, Miquel Vila, Celine Perier
In recent years, several important advances have been made in our understanding of the pathways that lead to cell dysfunction and death in Parkinson's disease (PD) and Huntington's disease (HD). Despite distinct clinical and pathological features, these two neurodegenerative diseases share critical processes, such as the presence of misfolded and/or aggregated proteins, oxidative stress, and mitochondrial anomalies. Even though the mitochondria are commonly regarded as the "powerhouses" of the cell, they are involved in a multitude of cellular events such as heme metabolism, calcium homeostasis, and apoptosis...
2018: Frontiers in Neuroscience
David C Schöndorf, Dina Ivanyuk, Pascale Baden, Alvaro Sanchez-Martinez, Silvia De Cicco, Cong Yu, Ivana Giunta, Lukas K Schwarz, Gabriele Di Napoli, Vasiliki Panagiotakopoulou, Sigrun Nestel, Marcus Keatinge, Jan Pruszak, Oliver Bandmann, Bernd Heimrich, Thomas Gasser, Alexander J Whitworth, Michela Deleidi
While mitochondrial dysfunction is emerging as key in Parkinson's disease (PD), a central question remains whether mitochondria are actual disease drivers and whether boosting mitochondrial biogenesis and function ameliorates pathology. We address these questions using patient-derived induced pluripotent stem cells and Drosophila models of GBA-related PD (GBA-PD), the most common PD genetic risk. Patient neurons display stress responses, mitochondrial demise, and changes in NAD+ metabolism. NAD+ precursors have been proposed to ameliorate age-related metabolic decline and disease...
June 5, 2018: Cell Reports
Amy K Reeve, John P Grady, Eve M Cosgrave, Emma Bennison, Chun Chen, Philippa D Hepplewhite, Christopher M Morris
Mitochondrial dysfunction within the cell bodies of substantia nigra neurons is prominent in both ageing and Parkinson's disease. The loss of dopaminergic substantia nigra neurons in Parkinson's disease is associated with loss of synapses within the striatum, and this may precede neuronal loss. We investigated whether mitochondrial changes previously reported within substantia nigra neurons were also seen within the synapses and axons of these neurons. Using high resolution quantitative fluorescence immunohistochemistry we determined mitochondrial density within remaining dopaminergic axons and synapses, and quantified deficiencies of mitochondrial Complex I and Complex IV in these compartments...
2018: NPJ Parkinson's Disease
Sandra M Cardoso, Nuno Empadinhas
The brain is an immunologically active organ where neurons and glia cells orchestrate complex innate immune responses against infections and injuries. Neuronal responses involve Toll-like or Nod-like receptors and the secretion of antimicrobial peptides and cytokines. The endosymbiotic theory for the evolutionary origin of mitochondria from primitive bacteria, suggests that they may have also retained the capacity to activate neuronal innate immunity. In fact, it was shown that mitochondrial damage-associated molecular patterns could signal and activate innate immunity and inflammation...
2018: Frontiers in Physiology
Ye Xi, Dayun Feng, Kai Tao, Ronglin Wang, Yajun Shi, Huaizhou Qin, Michael P Murphy, Qian Yang, Gang Zhao
Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra compacta (SNc). Although mitochondrial dysfunction is the critical factor in the pathogenesis of PD, the underlying molecular mechanisms are not well understood, and as a result, effective medical interventions are lacking. Mitochondrial fission and fusion play important roles in the maintenance of mitochondrial function and cell viability. Here, we investigated the effects of MitoQ, a mitochondria-targeted antioxidant, in 6-hydroxydopamine (6-OHDA)-induced in vitro and in vivo PD models...
May 26, 2018: Biochimica et Biophysica Acta
Tom Cornelissen, Sven Vilain, Katlijn Vints, Natalia Gounko, Patrik Verstreken, Wim Vandenberghe
Mutations in the genes for PINK1 and parkin cause Parkinson's disease. PINK1 and parkin cooperate in the selective autophagic degradation of damaged mitochondria (mitophagy) in cultured cells. However, evidence for their role in mitophagy in vivo is still scarce. Here, we generated a Drosophila model expressing the mitophagy probe mt-Keima. Using live mt-Keima imaging and correlative light and electron microscopy (CLEM) we show that mitophagy occurs in muscle cells and dopaminergic neurons in vivo, even in the absence of exogenous mitochondrial toxins...
May 29, 2018: ELife
Matteo Audano, Anja Schneider, Nico Mitro
In the last decades, lysosomes and mitochondria were considered distinct and physically separated organelles involved in different cellular functions. While lysosomes were thought to exclusively be the rubbish dump of the cell involved in the degradation of proteins and other cell compartments, mitochondria were considered solely involved in the oxidation of energy substrate to get ATP, together with other minor duties. Nowadays, our view of these organelles is profoundly changed since studies demonstrated that mitochondria and lysosome are mutually functional, maintaining proper cell homeostasis...
May 27, 2018: Journal of Neurochemistry
Emmanuel Quansah, Wouter Peelaerts, J William Langston, David K Simon, Jerry Colca, Patrik Brundin
Several molecular pathways are currently being targeted in attempts to develop disease-modifying therapies to slow down neurodegeneration in Parkinson's disease. Failure of cellular energy metabolism has long been implicated in sporadic Parkinson's disease and recent research on rare inherited forms of Parkinson's disease have added further weight to the importance of energy metabolism in the disease pathogenesis. There exists a new class of anti-diabetic insulin sensitizers in development that inhibit the mitochondrial pyruvate carrier (MPC), a protein which mediates the import of pyruvate across the inner membrane of mitochondria...
May 24, 2018: Molecular Neurodegeneration
José Pedro Castro, Kristina Wardelmann, Tilman Grune, André Kleinridders
The brain orchestrates organ function and regulates whole body metabolism by the concerted action of neurons and glia cells in the central nervous system. To do so, the brain has tremendously high energy consumption and relies mainly on glucose utilization and mitochondrial function in order to exert its function. As a consequence of high rate metabolism, mitochondria in the brain accumulate errors over time, such as mitochondrial DNA (mtDNA) mutations, reactive oxygen species, and misfolded and aggregated proteins...
2018: Frontiers in Endocrinology
Anthea Di Rita, Pasquale D'Acunzo, Luca Simula, Silvia Campello, Flavie Strappazzon, Francesco Cecconi
Therapeutic strategies are needed to protect dopaminergic neurons in Parkinson's disease (PD) patients. Oxidative stress caused by dopamine may play an important role in PD pathogenesis. Selective autophagy of mitochondria (mitophagy), mainly regulated by PINK1 and PARKIN, plays an important role in the maintenance of cell homeostasis. Mutations in those genes cause accumulation of damaged mitochondria, leading to nigral degeneration and early-onset PD. AMBRA1ActA is a fusion protein specifically expressed at the mitochondria, and whose expression has been shown to induce a powerful mitophagy in mammalian cells...
2018: Frontiers in Cellular Neuroscience
Mario Rango, Nereo Bresolin
This paper reconsiders the role of mitochondria in aging and in Parkinson's Disease (PD). The most important risk factor for PD is aging. Alterations in mitochondrial activity are typical of aging. Mitochondrial aging is characterized by decreased oxidative phosphorylation, proteasome activity decrease, altered autophagy, and mitochondrial dysfunction. Beyond declined oxidative phosphorylation, mitochondrial dysfunction consists of a decline of beta-oxidation as well as of the Krebs cycle. Not inherited mitochondrial DNA (mtDNA) mutations are acquired over time and parallel the decrease in oxidative phosphorylation...
May 11, 2018: Genes
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