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parkin and parkinson disease

Kelly L Stauch, Lance M Villeneuve, Phillip R Purnell, Sanjit Pandey, Chittibabu Guda, Howard S Fox
This article reports changes in the striatal non-synaptic mitochondrial proteome of DJ-1, Parkin, and PINK1 knockout (KO) rats at 3 months of age. DJ-1, Parkin, and PINK1 mutations cause autosomal-recessive parkinsonism. It is thought that loss of function of these proteins contributes to the onset and pathogenesis of Parkinson׳s disease (PD). As DJ-1, Parkin, and PINK1 have functions in the regulation of mitochondria, the dataset generated here highlights protein expression changes, which can be helpful for understanding pathological mitochondrial alterations...
December 2016: Data in Brief
Mauricio P Cunha, Francis L Pazini, Vicente Lieberknecht, Josiane Budni, Ágatha Oliveira, Júlia M Rosa, Gianni Mancini, Leidiane Mazzardo, André R Colla, Marina C Leite, Adair R S Santos, Daniel F Martins, Andreza F de Bem, Carlos Alberto S Gonçalves, Marcelo Farina, Ana Lúcia S Rodrigues
The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces motor and nonmotor dysfunctions resembling Parkinson's disease (PD); however, studies investigating the effects of 1-methyl-4-phenylpyridinium (MPP(+)), an active oxidative product of MPTP, are scarce. This study investigated the behavioral and striatal neurochemical changes (related to oxidative damage, glial markers, and neurotrophic factors) 24 h after intracerebroventricular administration of MPP(+) (1.8-18 μg/mouse) in C57BL6 mice...
October 8, 2016: Molecular Neurobiology
Rijan Bajracharya, J William O Ballard
Dietary management plays a key role in the treatment of many diseases. However, no prospective studies have critically investigated the potential for dietary modification to delay the onset, or slow the progression, of Parkinson's Disease (PD). To study whether manipulating the Protein to Carbohydrate (P:C) ratio in the diet could affect the progression of PD, we compared Drosophila melanogaster parkin null mutants and their experimental controls fed with diets differing in their P:C ratio. We considered lifespan and feeding behaviors as well as motor and cellular functions on the 1:2 and 1:16 P:C diets...
October 6, 2016: Mechanisms of Ageing and Development
Sandra-Fausia Soukup, Sabine Kuenen, Roeland Vanhauwaert, Julia Manetsberger, Sergio Hernández-Díaz, Jef Swerts, Nils Schoovaerts, Sven Vilain, Natalia V Gounko, Katlijn Vints, Ann Geens, Bart De Strooper, Patrik Verstreken
Synapses are often far from the soma and independently cope with proteopathic stress induced by intense neuronal activity. However, how presynaptic compartments turn over proteins is poorly understood. We show that the synapse-enriched protein EndophilinA, thus far studied for its role in endocytosis, induces macroautophagy at presynaptic terminals. We find that EndophilinA executes this unexpected function at least partly independent of its role in synaptic vesicle endocytosis. EndophilinA-induced macroautophagy is activated when the kinase LRRK2 phosphorylates the EndophilinA-BAR domain and is blocked in animals where EndophilinA cannot be phosphorylated...
October 5, 2016: Neuron
Vaishali Kakkar, E F Elsiena Kuiper, Abhinav Pandey, Ineke Braakman, Harm H Kampinga
Parkinson's disease is one of the most common neurodegenerative disorders and several mutations in different genes have been identified to contribute to the disease. A loss of function parkin RING1 domain mutant (C289G) is associated with autosomal-recessive juvenile-onset Parkinsonism (AR-JP) and displays altered solubility and sequesters into aggregates. Single overexpression of almost each individual member of the Hsp40 (DNAJ) family of chaperones efficiently reduces parkin C289G aggregation and requires interaction with and activity of endogenously expressed Hsp70 s...
October 7, 2016: Scientific Reports
Gian D Pal, Deborah Hall, Bichun Ouyang, Jessica Phelps, Roy Alcalay, Michael W Pauciulo, William C Nichols, Lorraine Clark, Helen Mejia-Santana, Lucia Blasucci, Christopher G Goetz, Cynthia Comella, Amy Colcher, Ziv Gan-Or, Guy A Rouleau, Karen Marder
OBJECTIVE: In a cohort of patients with young-onset Parkinson's disease (PD), the authors assessed (1) the prevalence of genetic mutations in those who enrolled in deep brain stimulation (DBS) programs compared with those who did not enroll DBS programs and (2) specific genetic and clinical predictors of DBS enrollment. METHODS: Subjects were participants from 3 sites (Columbia University, Rush University, and the University of Pennsylvania) in the Consortium on Risk for Early Onset Parkinson's Disease (CORE-PD) who had an age at onset < 51 years...
September 2016: Movement Disorders Clinical Practice
Patricia Villacé, Rosa M Mella, Meritxell Roura-Ferrer, María Valcárcel, Clarisa Salado, Amaia Castilla, Danel Kortazar
Parkinson disease (PD) is a prevalent neurodegenerative disease characterized by selective degeneration of dopaminergic neurons in the substantia nigra, causing tremor and motor impairment. Parkin protein, whose mutants are the cause of Parkinson disease type 2 (PARK2), has been mechanistically linked to the regulation of apoptosis and the turnover of damaged mitochondria. Several studies have implicated aberrant mitochondria as a key contributor to the development of PD. In the attempt to discover new drugs, high-content cell-based assays are becoming more important to mimic the nature of biological processes and their diversifications in diseases and will be essential for lead identification and the optimization of therapeutic candidates...
October 4, 2016: Journal of Biomolecular Screening
Eleftheria Letsiou, Saad Sammani, Huashan Wang, Patrick Belvitch, Steven M Dudek
The acute respiratory distress syndrome (ARDS) is a serious condition resulting from direct or indirect lung injury that is associated with high mortality and morbidity. A key biological event in the pathogenesis of the acute lung injury (ALI) that causes acute respiratory distress syndrome is activation of the lung endothelium cells (ECs), which is triggered by a variety of inflammatory insults leading to barrier disruption and excessive accumulation of neutrophils. Recently, we demonstrated that imatinib protects against lipopolysaccharide (LPS)-induced EC activation by inhibiting c-Abl kinase...
September 13, 2016: Translational Research: the Journal of Laboratory and Clinical Medicine
Sun Young Chung, Sarah Kishinevsky, Joseph R Mazzulli, John Graziotto, Ana Mrejeru, Eugene V Mosharov, Lesly Puspita, Parvin Valiulahi, David Sulzer, Teresa A Milner, Tony Taldone, Dimitri Krainc, Lorenz Studer, Jae-Won Shim
Parkinson's disease (PD) is characterized by the selective loss of dopamine neurons in the substantia nigra; however, the mechanism of neurodegeneration in PD remains unclear. A subset of familial PD is linked to mutations in PARK2 and PINK1, which lead to dysfunctional mitochondria-related proteins Parkin and PINK1, suggesting that pathways implicated in these monogenic forms could play a more general role in PD. We demonstrate that the identification of disease-related phenotypes in PD-patient-specific induced pluripotent stem cell (iPSC)-derived midbrain dopamine (mDA) neurons depends on the type of differentiation protocol utilized...
October 11, 2016: Stem Cell Reports
Pascale Baden, Michela Deleidi
Mitochondrial antigens can be presented by MHC molecules and initiate adaptive immune responses but the mechanisms of mitochondrial antigen presentation (MitAP) have remained mostly unknown. A recent study proposes a new model whereby MitAP is mediated by a vesicle transport pathway that is suppressed by the Parkinson's disease (PD) associated proteins PTEN-induced putative kinase 1 (PINK1) and Parkin. This discovery brings a new perspective on the link between mitochondrial dysfunction and autoimmunity in PD...
September 13, 2016: Trends in Immunology
Chung-Han Hsieh, Atossa Shaltouki, Ashley E Gonzalez, Alexandre Bettencourt da Cruz, Lena F Burbulla, Erica St Lawrence, Birgitt Schüle, Dimitri Krainc, Theo D Palmer, Xinnan Wang
Mitochondrial movements are tightly controlled to maintain energy homeostasis and prevent oxidative stress. Miro is an outer mitochondrial membrane protein that anchors mitochondria to microtubule motors and is removed to stop mitochondrial motility as an early step in the clearance of dysfunctional mitochondria. Here, using human induced pluripotent stem cell (iPSC)-derived neurons and other complementary models, we build on a previous connection of Parkinson's disease (PD)-linked PINK1 and Parkin to Miro by showing that a third PD-related protein, LRRK2, promotes Miro removal by forming a complex with Miro...
August 25, 2016: Cell Stem Cell
Gunnar F Kwakye, Rachael A McMinimy, Michael Aschner
Human disease commonly manifests as a result of complex genetic and environmental interactions. In the case of neurodegenerative diseases, such as Parkinson's disease (PD), understanding how environmental exposures collude with genetic polymorphisms in the central nervous system to cause dysfunction is critical in order to develop better treatment strategies, therapies, and a more cohesive paradigm for future research. The intersection of genetics and the environment in disease etiology is particularly relevant in the context of their shared pathophysiological mechanisms...
September 9, 2016: Neurochemical Research
Hongjun Xie, Jie Wu
Silica nanoparticles (SiO2-NPs) are widely applied in diagnosis, imaging, and drug delivery of central nervous diseases. Previously, we found that SiO2-NPs enter the brain and, more specifically, the dopaminergic neurons in the striatum. Whether SiO2-NPs have neurotoxicity and contribute to development of Parkinson's disease (PD) remains unclear. In this study, we investigated the effect of SiO2-NPs on PC12 cells, a dopaminergic neuron-like cell line. We showed that SiO2-NPs up-regulated α-synuclein expression, and N-acetyl cysteine reduced α-synuclein...
October 25, 2016: Chemico-biological Interactions
Julian L Klosowiak, Sungjin Park, Kyle P Smith, Michael E French, Pamela J Focia, Douglas M Freymann, Sarah E Rice
Hereditary Parkinson's disease is commonly caused by mutations in the protein kinase PINK1 or the E3 ubiquitin ligase Parkin, which function together to eliminate damaged mitochondria. PINK1 phosphorylates both Parkin and ubiquitin to stimulate ubiquitination of dozens of proteins on the surface of the outer mitochondrial membrane. However, the mechanisms by which Parkin recognizes specific proteins for modification remain largely unexplored. Here, we show that the C-terminal GTPase (cGTPase) of the Parkin primary substrate human Miro is necessary and sufficient for efficient ubiquitination...
2016: Scientific Reports
Francesca Morgante, Alfonso Fasano, Monia Ginevrino, Simona Petrucci, Lucia Ricciardi, Francesco Bove, Chiara Criscuolo, Marcello Moccia, Anna De Rosa, Chiara Sorbera, Anna Rita Bentivoglio, Paolo Barone, Giuseppe De Michele, Maria Teresa Pellecchia, Enza Maria Valente
OBJECTIVE: The aim of this multicenter, case-control study was to investigate the prevalence and severity of impulsive-compulsive behaviors (ICBs) in a cohort of patients with parkin-associated Parkinson disease (PD) compared to a group of patients without the mutation. METHODS: We compared 22 patients with biallelic parkin mutations (parkin-PD) and 26 patients negative for parkin, PINK1, DJ-1, and GBA mutations (PD-NM), matched for age at onset, disease duration, levodopa, and dopamine agonist equivalent daily dose...
October 4, 2016: Neurology
Cornelia Rüb, Anne Wilkening, Wolfgang Voos
Mitochondrial dysfunction represents a prominent pathological feature in many neurodegenerative diseases, particularly in Parkinson's disease (PD). Mutations in the genes encoding the proteins Pink1 and Parkin have been identified as genetic risk factors in familiar cases of PD. Research during the last decade has identified both proteins as crucial components of an organellar quality control system that contributes to the maintenance of mitochondrial function in healthy cells. The Pink1/Parkin system acts as a sensor for mitochondrial quality and is activated, in particular, after the loss of the electric potential across the inner mitochondrial membrane...
September 2, 2016: Cell and Tissue Research
Rosalind F Roberts, Edward A Fon
In a recent paper published in Cell, Matheoud et al. demonstrated that, in response to cellular stress, self-antigens can be extracted from mitochondria via mitochondrial-derived vesicles and presented at the cell surface to trigger an immune response; this pathway, termed mitochondrial antigen presentation (MitAP), is repressed by PINK1 and Parkin. These findings implicate autoimmune mechanisms in Parkinson's disease.
September 2, 2016: Cell Research
K Gaweda-Walerych, F Mohagheghi, C Zekanowski, E Buratti
We have analyzed the impact of Parkinson's disease (PD)-related genetic variants on splicing using dedicated minigene assays. Out of 14 putative splicing variants in 5 genes (PINK1, [PTEN induced kinase 1]; LRPPRC, [leucine-rich pentatricopeptide repeat containing protein]; TFAM, [mitochondrial transcription factor A]; PARK2, [parkin RBR E3 ubiquitin protein ligase]; and HSPA9, [heat shock protein family A (Hsp70) member 9]) 4 LRPPRC variants, (IVS32-3C>T, IVS35+14C>T, IVS35+15C>T, and IVS9+30A>G) influenced pre-messenger RNA splicing by modulating the inclusion of the respective exons...
July 28, 2016: Neurobiology of Aging
Joseph R Patterson, Elizabeth J Kim, John L Goudreau, Keith J Lookingland
Parkinson disease (PD) is characterized by progressive neuronal degeneration, in particular nigrostriatal dopamine (NSDA) neurons and consequent deficits in movement. In mice and non-human primates, NSDA neurons preferentially degenerate following exposure to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Tuberoinfundibular (TI) DA neurons, in contrast, appear to be unaffected in PD and recover following acute MPTP exposure-induced injury (Behrouz et al., 2007; Benskey et al., 2012)...
August 23, 2016: Brain Research
S Torii, S Kasai, A Suzuki, Y Todoroki, K Yokozawa, K-I Yasumoto, N Seike, H Kiyonari, Y Mukumoto, A Kakita, K Sogawa
Inhibitory PAS domain protein (IPAS), a repressor of hypoxia-inducible factor-dependent transcription under hypoxia, was found to exert pro-apoptotic activity in oxidative stress-induced cell death. However, physiological and pathological processes associated with this activity are not known. Here we show that IPAS is a key molecule involved in neuronal cell death in Parkinson's disease (PD). IPAS was ubiquitinated by Parkin for proteasomal degradation following carbonyl cyanide m-chlorophenyl hydrazone treatment...
2015: Cell Death Discovery
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