Monitoring mitochondrial dynamics and complex I dysfunction in neurons: implications for Parkinson's disease

2013 ◽  
Vol 41 (6) ◽  
pp. 1618-1624 ◽  
Author(s):  
Eve M. Simcox ◽  
Amy Reeve ◽  
Doug Turnbull
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Complex I ◽  
Neurodegenerative Disorder ◽  
Mitochondrial Dynamics ◽  
Cell Loss ◽  
Transport Chain ◽  
The Individual ◽  
And Function ◽  
Energy Dependent

Mitochondrial dynamics are essential for maintaining organelle stability and function. Through fission, fusion and mitophagic events, optimal populations of mitochondria are retained. Subsequently, alterations in such processes can have profound effects on the individual mitochondrion and the cell within which they reside. Neurons are post-mitotic energy-dependent cells and, as such, are particularly vulnerable to alterations in cellular bioenergetics and increased stress that may occur as a direct or indirect result of mitochondrial dysfunction. The trafficking of mitochondria to areas of higher energy requirements, such as synapses, where mitochondrial densities fluctuate, further highlights the importance of efficient mitochondrial dynamics in neurons. PD (Parkinson's disease) is a common progressive neurodegenerative disorder which is characterized by the loss of dopaminergic neurons within the substantia nigra. Complex I, the largest of all of the components of the electron transport chain is heavily implicated in PD pathogenesis. The exact series of events that lead to cell loss, however, are not fully elucidated, but are likely to involve dysfunction of mitochondria, their trafficking and dynamics.

A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson’s disease

2020 ◽  
Vol 12 (560) ◽  
pp. eaau3960
Author(s):  
Ibrahim Boussaad ◽  
Carolin D. Obermaier ◽  
Zoé Hanss ◽  
Dheeraj R. Bobbili ◽  
Silvia Bolognin ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Neurodegenerative Disorder ◽  
Neuronal Cell ◽  
Exon Skipping ◽  
Cell Loss ◽  
Genetically Engineered ◽  
Neuronal Precursor Cells

Parkinson’s disease (PD) is a heterogeneous neurodegenerative disorder with monogenic forms representing prototypes of the underlying molecular pathology and reproducing to variable degrees the sporadic forms of the disease. Using a patient-based in vitro model of PARK7-linked PD, we identified a U1-dependent splicing defect causing a drastic reduction in DJ-1 protein and, consequently, mitochondrial dysfunction. Targeting defective exon skipping with genetically engineered U1-snRNA recovered DJ-1 protein expression in neuronal precursor cells and differentiated neurons. After prioritization of candidate drugs, we identified and validated a combinatorial treatment with the small-molecule compounds rectifier of aberrant splicing (RECTAS) and phenylbutyric acid, which restored DJ-1 protein and mitochondrial dysfunction in patient-derived fibroblasts as well as dopaminergic neuronal cell loss in mutant midbrain organoids. Our analysis of a large number of exomes revealed that U1 splice-site mutations were enriched in sporadic PD patients. Therefore, our study suggests an alternative strategy to restore cellular abnormalities in in vitro models of PD and provides a proof of concept for neuroprotection based on precision medicine strategies in PD.

scholarly journals Graphene Oxide and Reduced Derivatives, as Powder or Film Scaffolds, Differentially Promote Dopaminergic Neuron Differentiation and Survival

2020 ◽  
Vol 14 ◽  
Author(s):  
Noela Rodriguez-Losada ◽  
Rune Wendelbob ◽  
M. Carmen Ocaña ◽  
Amelia Diaz Casares ◽  
Roberto Guzman de Villoría ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Graphene Oxide ◽  
Carbon Nanomaterials ◽  
Cell Loss ◽  
Synaptic Proteins ◽  
New Drugs ◽  
Neural Regeneration ◽  
Protein Levels ◽  
And Function

Emerging scaffold structures made of carbon nanomaterials, such as graphene oxide (GO) have shown efficient bioconjugation with common biomolecules. Previous studies described that GO promotes the differentiation of neural stem cells and may be useful for neural regeneration. In this study, we examined the capacity of GO, full reduced (FRGO), and partially reduced (PRGO) powder and film to support survival, proliferation, differentiation, maturation, and bioenergetic function of a dopaminergic (DA) cell line derived from the mouse substantia nigra (SN4741). Our results show that the morphology of the film and the species of graphene (GO, PRGO, or FRGO) influences the behavior and function of these neurons. In general, we found better biocompatibility of the film species than that of the powder. Analysis of cell viability and cytotoxicity showed good cell survival, a lack of cell death in all GO forms and its derivatives, a decreased proliferation, and increased differentiation over time. Neuronal maturation of SN4741 in all GO forms, and its derivatives were assessed by increased protein levels of tyrosine hydroxylase (TH), dopamine transporter (DAT), the glutamate inward rectifying potassium channel 2 (GIRK2), and of synaptic proteins, such as synaptobrevin and synaptophysin. Notably, PRGO-film increased the levels of Tuj1 and the expression of transcription factors specific for midbrain DA neurons, such as Pitx3, Lmx1a, and Lmx1b. Bioenergetics and mitochondrial dysfunction were evaluated by measuring oxygen consumption modified by distinct GO species and were different between powder and film for the same GO species. Our results indicate that PRGO-film was the best GO species at maintaining mitochondrial function compared to control. Finally, different GO forms, and particularly PRGO-film was also found to prevent the loss of DA cells and the decrease of the α-synuclein (α-syn) in a molecular environment where oxidative stress has been induced to model Parkinson's disease. In conclusion, PRGO-film is the most efficient graphene species at promoting DA differentiation and preventing DA cell loss, thus becoming a suitable scaffold to test new drugs or develop constructs for Parkinson's disease cell replacement therapy.

scholarly journals Treatment of Parkinson's Disease

2003 ◽  
Vol 30 (S1) ◽  
pp. S27-S33 ◽  
Author(s):  
W.R. Wayne Martin ◽  
Marguerite Wieler
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Functional Disability ◽  
Neurodegenerative Disorder ◽  
Holistic Approach ◽  
Symptomatic Treatment ◽  
Therapeutic Interventions ◽  
Dopaminergic Therapy ◽  
Comprehensive Management ◽  
The Individual

Parkinson's disease is a progressive neurodegenerative disorder that demands a holistic approach to treatment. Both pharmacologic and nonpharmacologic interventions play an important role in the comprehensive management of this disorder. While levodopa remains the single most effective medication for symptomatic treatment, dopamine agonists are playing an increasingly important role. Motor complications of dopaminergic therapy are a significant issue, particularly in patients with more advanced disease who have been on levodopa for several years. All therapeutic interventions must be tailored to the individual and modified as the disease progresses, with the goal of minimizing significant functional disability as much as possible.

scholarly journals Oligomerization of Lrrk controls actin severing and α-synuclein neurotoxicity in vivo

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Souvarish Sarkar ◽  
Farah Bardai ◽  
Abby L. Olsen ◽  
Kelly M. Lohr ◽  
Ying-Yi Zhang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Degeneration ◽  
Mitochondrial Dynamics ◽  
Actin Dynamics ◽  
Human Neurons ◽  
Biochemical Analyses ◽  
And Function

Abstract Background Mutations in LRRK2 are the most common cause of familial Parkinson’s disease and typically cause disease in the context of abnormal aggregation and deposition of α-synuclein within affected brain tissue. Methods We combine genetic analysis of Lrrk-associated toxicity in a penetrant Drosophila model of wild type human α-synuclein neurotoxicity with biochemical analyses and modeling of LRRK2 toxicity in human neurons and transgenic mouse models. Results We demonstrate that Lrrk and α-synuclein interact to promote neuronal degeneration through convergent effects on the actin cytoskeleton and downstream dysregulation of mitochondrial dynamics and function. We find specifically that monomers and dimers of Lrrk efficiently sever actin and promote normal actin dynamics in vivo. Oligomerization of Lrrk, which is promoted by dominant Parkinson’s disease-causing mutations, reduces actin severing activity in vitro and promotes excess stabilization of F-actin in vivo. Importantly, a clinically protective Lrrk mutant reduces oligomerization and α-synuclein neurotoxicity. Conclusions Our findings provide a specific mechanistic link between two key molecules in the pathogenesis of Parkinson’s disease, α-synuclein and LRRK2, and suggest potential new approaches for therapy development.

scholarly journals A Multi-Scale Computational Model of Excitotoxic Loss of Dopaminergic Cells in Parkinson’s Disease

2020 ◽  
Author(s):  
Vignayanandam R. Muddapu ◽  
V. Srinivasa Chakravarthy
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Computational Model ◽  
Neurodegenerative Disorder ◽  
Cell Loss ◽  
Therapeutic Interventions ◽  
Substantia Nigra Pars Compacta ◽  
Therapeutic Effects ◽  
Multi Scale

ABSTRACTParkinson’s disease (PD) is a neurodegenerative disorder caused by loss of dopaminergic neurons in Substantia Nigra pars compacta (SNc). Although the exact cause of the cell death is not clear, the hypothesis that metabolic deficiency is a key facor has been gaining attention in the recent years. In the present study, we investigate this hypothesis using a multi-scale computational model of the subsystem of the basal ganglia comprising Subthalamic Nucleus (STN), Globus Pallidus externa (GPe) and SNc. The model is a multiscale model in that interactions among the three nuclei are simulated using more abstract Izhikevich neuron models, while the molecular pathways involved in cell death of SNc neurons are simulated in terms of detailed chemical kinetics. Simulation results obtained from the proposed model showed that energy deficiencies occurring at cellular and network levels could precipitate the excitotoxic loss of SNc neurons in PD. At the subcellular level, the models show how calcium elevation leads to apoptosis of SNc neurons. The therapeutic effects of several neuroprotective interventions are also simulated in the model. From neuroprotective studies, it was clear that glutamate inhibition and apoptotic signal blocker therapies were able to halt the progression of SNc cell loss when compared to other therapeutic interventions, which only slows down the progression of SNc cell loss.

scholarly journals Impaired mitochondrial–endoplasmic reticulum interaction and mitophagy in Miro1-mutant neurons in Parkinson’s disease

2020 ◽  
Vol 29 (8) ◽  
pp. 1353-1364 ◽  
Author(s):  
Clara Berenguer-Escuder ◽  
Dajana Grossmann ◽  
Paul Antony ◽  
Giuseppe Arena ◽  
Kobi Wasner ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Endoplasmic Reticulum ◽  
Live Cell Imaging ◽  
Cell Imaging ◽  
Mitochondrial Dynamics ◽  
Live Cell ◽  
Calcium Handling ◽  
Imaging Results ◽  
And Function

Abstract Mitochondrial Rho GTPase 1 (Miro1) protein is a well-known adaptor for mitochondrial transport and also regulates mitochondrial quality control and function. Furthermore, Miro1 was associated with mitochondrial-endoplasmic reticulum (ER) contact sites (MERCs), which are key regulators of cellular calcium homeostasis and the initiation of autophagy. Impairments of these mechanisms were linked to neurodegeneration in Parkinson’s disease (PD). We recently revealed that PD fibroblasts harboring Miro1 mutations displayed dysregulations in MERC organization and abundance, affecting mitochondrial homeostasis and clearance. We hypothesize that mutant Miro1 impairs the function of MERCs and mitochondrial dynamics, altering neuronal homeostasis and integrity in PD. PD skin fibroblasts harboring the Miro1-R272Q mutation were differentiated into patient-derived neurons. Live-cell imaging and immunocytochemistry were used to study mitophagy and the organization and function of MERCs. Markers of autophagy or mitochondrial function were assessed by western blotting. Quantification of organelle juxtapositions revealed an increased number of MERCs in patient-derived neurons. Live-cell imaging results showed alterations of mitochondrial dynamics and increased sensitivity to calcium stress, as well as reduced mitochondrial clearance. Finally, western blot analysis indicated a blockage of the autophagy flux in Miro1-mutant neurons. Miro1-mutant neurons display altered ER-mitochondrial tethering compared with control neurons. This alteration likely interferes with proper MERC function, contributing to a defective autophagic flux and cytosolic calcium handling capacity. Moreover, mutant Miro1 affects mitochondrial dynamics in neurons, which may result in disrupted mitochondrial turnover and altered mitochondrial movement.

scholarly journals αSynuclein and Mitochondrial Dysfunction: A Pathogenic Partnership in Parkinson’s Disease?

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
David Protter ◽  
Charmaine Lang ◽  
Antony A. Cooper
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Molecular Mechanisms ◽  
Nitrosative Stress ◽  
Neurodegenerative Disorder ◽  
Mitochondrial Dynamics ◽  
Term Therapy ◽  
Central Component ◽  
Cellular Targets

Parkinson’s Disease (PD) is a complex, chronic, progressive, and debilitating neurodegenerative disorder. Neither a cure nor effective long-term therapy exist and the lack of knowledge of the molecular mechanisms responsible for PD development is a major impediment to therapeutic advances. The protein αSynuclein is a central component in PD pathogenesis yet its cellular targets and mechanism of toxicity remains unknown. Mitochondrial dysfunction is also a common theme in PD patients and this review explores the strong possibility that αSynuclein and mitochondrial dysfunction have an inter-relationship responsible for underlying the disease pathology. Amplifying cycles of mitochondrial dysfunction and αSynuclein toxicity can be envisaged, with either being the disease-initiating factor yet acting together during disease progression. Multiple potential mechanisms exist in which mitochondrial dysfunction and αSynuclein could interact to exacerbate their neurodegenerative properties. Candidates discussed within this review include autophagy, mitophagy, mitochondrial dynamics/fusion/fission, oxidative stress and reactive oxygen species, endoplasmic reticulum stress, calcium, nitrosative stress and αSynuclein Oligomerization.

scholarly journals Current Progress of Mitochondrial Quality Control Pathways Underlying the Pathogenesis of Parkinson’s Disease

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Xue Jiang ◽  
Tao Jin ◽  
Haining Zhang ◽  
Jing Miao ◽  
Xiuzhen Zhao ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Quality Control ◽  
Mitochondrial Dysfunction ◽  
Neurodegenerative Disorder ◽  
Mitochondrial Dynamics ◽  
Alpha Synuclein ◽  
Substantia Nigra Pars Compacta ◽  
Toxic Metabolite ◽  
Mitochondrial Quality Control

Parkinson’s disease (PD), clinically characterized by motor and nonmotor symptoms, is a common progressive and multisystem neurodegenerative disorder, which is caused by both genetic and environmental risk factors. The main pathological features of PD are the loss of dopaminergic (DA) neurons and the accumulation of alpha-synuclein (α-syn) in the residual DA neurons in the substantia nigra pars compacta (SNpc). In recent years, substantial progress has been made in discovering the genetic factors of PD. In particular, a total of 19 PD-causing genes have been unraveled, among which some members have been regarded to be related to mitochondrial dysfunction. Mitochondria are key regulators of cellular metabolic activity and are critical for many important cellular processes including energy metabolism and even cell death. Their normal function is basically maintained by the mitochondrial quality control (MQC) mechanism. Accordingly, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a kind of neurotoxin, exerts its neurotoxic effects at least partially by producing its toxic metabolite, namely, 1-methyl-4-phenylpyridine (MPP+), which in turn causes mitochondrial dysfunction by inhibiting complex I and mimicking the key features of PD pathogenesis. This review focused on three main aspects of the MQC signaling pathways, that is, mitochondrial biogenesis, mitochondrial dynamics, and mitochondrial autophagy; hence, it demonstrates in detail how genetic and environmental factors result in PD pathogenesis by interfering with MQC pathways, thereby hopefully contributing to the discovery of novel potential therapeutic targets for PD.

scholarly journals Deficiency of Parkinson’s disease-related gene Fbxo7 is associated with impaired mitochondrial metabolism by PARP activation

2016 ◽  
Vol 24 (1) ◽  
pp. 120-131 ◽  
Author(s):  
Marta Delgado-Camprubi ◽  
Noemi Esteras ◽  
Marc PM Soutar ◽  
Helene Plun-Favreau ◽  
Andrey Y Abramov
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Complex I ◽  
Parp Inhibitor ◽  
Parp Activation ◽  
Mitochondrial Homeostasis ◽  
Transport Chain ◽  
Ubiquitin Ligase Complex ◽  
F Box Protein ◽  
Redox Index

Abstract The Parkinson’s disease (PD)-related protein F-box only protein 7 (Fbxo7) is the substrate-recognition component of the Skp1-Cullin-F-box protein E3 ubiquitin ligase complex. We have recently shown that PD-associated mutations in Fbxo7 disrupt mitochondrial autophagy (mitophagy), suggesting a role for Fbxo7 in modulating mitochondrial homeostasis. Here we report that Fbxo7 deficiency is associated with reduced cellular NAD+ levels, which results in increased mitochondrial NADH redox index and impaired activity of complex I in the electron transport chain. Under these conditions of compromised respiration, mitochondrial membrane potential and ATP contents are reduced, and cytosolic reactive oxygen species (ROS) production is increased. ROS activates poly (ADP-ribose) polymerase (PARP) activity in Fbxo7-deficient cells. PARP inhibitor restores cellular NAD+ content and redox index and ATP pool, suggesting that PARP overactivation is cause of decreased complex I-driven respiration. These findings bring new insight into the mechanism of Fbxo7 deficiency, emphasising the importance of mitochondrial dysfunction in PD.

Advantages of Vasoactive Intestinal Peptide for the Future Treatment of Parkinson’s Disease

2019 ◽  
Vol 24 (39) ◽  
pp. 4693-4701 ◽  
Author(s):  
Orhan Tansel Korkmaz ◽  
Neşe Tunçel
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Vasoactive Intestinal Peptide ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Mitochondrial Dynamics ◽  
Beneficial Effects ◽  
Function Loss ◽  
Inflammatory Processes ◽  
Neuroprotective Actions

Parkinson’s disease is the second most common neurodegenerative disorder in adults over the age of 65. The characteristic symptoms of Parkinson’s disease, such as resting tremor, muscular rigidity, bradykinesia, postural instability and gait imbalance, are thought to be a result of the progressive degeneration of the dopaminergic neurons of the substantia nigra compacta, resulting in insufficient dopamine integrated signalling on GABAergic medium spiny neurons in the striatum. Despite tremendous research, the molecular mechanisms underlying the pathogenesis of neurodegeneration in Parkinson’s disease have remained largely unknown. Although a variety of possible pathogenic mechanisms have been proposed over the years, including excessive release of oxygen free radicals, impairment of mitochondrial function, loss of trophic support, abnormal kinase activity, disruption of calcium homeostasis, dysfunction of protein degradation and neuroinflammation, the pathogenesis is still largely uncertain, and there is currently no effective cure for Parkinson’s disease. To develop potential therapies for Parkinson’s disease, inflammatory processes, mitochondrial dynamics, oxidative stress, production of reactive aldehydes, excitotoxicity and synucleinopathies are to be targeted. In this respect, vasoactive intestinal peptide has beneficial effects that provide an advantage for the treatment of Parkinson’s disease. Vasoactive intestinal peptide is a major neuropeptide-neurotransmitter having antioxidant, anti-inflammatory, neurotropic, neuromodulator, and anti-apoptotic properties. In addition to its direct neuroprotective actions regulating the activity of astrocytes, microglia and brain mast cells, it also plays important roles for neuronal adaptation, maintenance and survival.

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