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https://www.readbyqxmd.com/read/28332488/parkinson-disease
#1
REVIEW
Werner Poewe, Klaus Seppi, Caroline M Tanner, Glenda M Halliday, Patrik Brundin, Jens Volkmann, Anette-Eleonore Schrag, Anthony E Lang
Parkinson disease is the second-most common neurodegenerative disorder that affects 2-3% of the population ≥65 years of age. Neuronal loss in the substantia nigra, which causes striatal dopamine deficiency, and intracellular inclusions containing aggregates of α-synuclein are the neuropathological hallmarks of Parkinson disease. Multiple other cell types throughout the central and peripheral autonomic nervous system are also involved, probably from early disease onwards. Although clinical diagnosis relies on the presence of bradykinesia and other cardinal motor features, Parkinson disease is associated with many non-motor symptoms that add to overall disability...
March 23, 2017: Nature Reviews. Disease Primers
https://www.readbyqxmd.com/read/28324489/monitoring-mitochondrial-changes-by-alteration-of-the-pink1-parkin-signaling-in-drosophila
#2
Tsuyoshi Inoshita, Kahori Shiba-Fukushima, Hongrui Meng, Nobutaka Hattori, Yuzuru Imai
Mitochondrial quality control is a key process in tissues with high energy demands, such as the brain and muscles. Recent studies using Drosophila have revealed that the genes responsible for familial forms of juvenile Parkinson's disease (PD), PINK1 and Parkin regulate mitochondrial function and motility. Cell biological analysis using mammalian cultured cells suggests that the dysregulation of mitophagy by PINK1 and Parkin leads to neurodegeneration in PD. In this chapter, we describe the methods to monitor mitochondrial morphology in the indirect flight muscles of adult Drosophila and Drosophila primary cultured neurons and the methods to analyze the motility of mitochondria in the axonal transport of living larval motor neurons...
March 22, 2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28323023/internalization-axonal-transport-and-release-of-fibrillar-forms-of-alpha-synuclein
#3
Gregor Bieri, Aaron D Gitler, Michel Brahic
Intra-neuronal protein aggregates made of fibrillar alpha-synuclein (α-syn) are the hallmark of Parkinson's disease (PD). With time, these aggregates spread through the brain following axonal projections. Understanding the mechanism of this spread is central to the study of the progressive nature of PD. Here we review data relevant to the uptake, transport and release of α-syn fibrils. We summarize several cell surface receptors that regulate the uptake of α-syn fibrils by neurons. The aggregates are then transported along axons, both in the anterograde and retrograde direction...
March 16, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28283599/dopamine-transporter-imaging-does-not-predict-the-number-of-nigral-neurons-in-parkinson-disease
#4
Laura Saari, Katri Kivinen, Maria Gardberg, Juho Joutsa, Tommi Noponen, Valtteri Kaasinen
OBJECTIVE: To examine possible associations between in vivo brain dopamine transporter SPECT imaging and substantia nigra pars compacta (SNc) neuronal survival in Parkinson disease (PD). METHODS: Nigral neuron numbers were calculated for 18 patients (11 patients with neuropathologically confirmed PD) who had been examined with dopamine transporter (DAT) SPECT before death. Correlation analyses between SNc tyrosine hydroxylase (TH)-positive and neuromelanin-containing neuron counts and DAT striatal specific binding ratios (SBRs) were performed with semiquantitative region of interest-based and voxel-based analyses...
March 10, 2017: Neurology
https://www.readbyqxmd.com/read/28086964/anti-%C3%AE-synuclein-immunotherapy-reduces-%C3%AE-synuclein-propagation-in-the-axon-and-degeneration-in-a-combined-viral-vector-and-transgenic-model-of-synucleinopathy
#5
Brian Spencer, Elvira Valera, Edward Rockenstein, Cassia Overk, Michael Mante, Anthony Adame, Wagner Zago, Peter Seubert, Robin Barbour, Dale Schenk, Dora Games, Robert A Rissman, Eliezer Masliah
Neurodegenerative disorders such as Parkinson's Disease (PD), PD dementia (PDD) and Dementia with Lewy bodies (DLB) are characterized by progressive accumulation of α-synuclein (α-syn) in neurons. Recent studies have proposed that neuron-to-neuron propagation of α-syn plays a role in the pathogenesis of these disorders. We have previously shown that antibodies against the C-terminus of α-syn reduce the intra-neuronal accumulation of α-syn and related deficits in transgenic models of synucleinopathy, probably by abrogating the axonal transport and accumulation of α-syn in in vivo models...
January 13, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28012891/altered-microtubule-dynamics-in-neurodegenerative-disease-therapeutic-potential-of-microtubule-stabilizing-drugs
#6
Kurt R Brunden, Virginia M-Y Lee, Amos B Smith, John Q Trojanowski, Carlo Ballatore
Many neurodegenerative diseases are characterized by deficiencies in neuronal axonal transport, a process in which cellular cargo is shuttled with the aid of molecular motors from the cell body to axonal termini and back along microtubules (MTs). Proper axonal transport is critical to the normal functioning of neurons, and impairments in this process could contribute to the neuronal damage and death that is characteristic of neurodegenerative disease. Although the causes of axonal transport abnormalities may vary among the various neurodegenerative conditions, in many cases it appears that the transport deficiencies result from a diminution of axonal MT stability...
December 22, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/28004277/tauroursodeoxycholic-bile-acid-arrests-axonal-degeneration-by-inhibiting-the-unfolded-protein-response-in-x-linked-adrenoleukodystrophy
#7
Nathalie Launay, Montserrat Ruiz, Laia Grau, Francisco J Ortega, Ekaterina V Ilieva, Juan José Martínez, Elena Galea, Isidre Ferrer, Erwin Knecht, Aurora Pujol, Stéphane Fourcade
The activation of the highly conserved unfolded protein response (UPR) is prominent in the pathogenesis of the most prevalent neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), which are classically characterized by an accumulation of aggregated or misfolded proteins. This activation is orchestrated by three endoplasmic reticulum (ER) stress sensors: PERK, ATF6 and IRE1. These sensors transduce signals that induce the expression of the UPR gene programme...
February 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/27956085/effects-of-%C3%AE-synuclein-on-axonal-transport
#8
Laura A Volpicelli-Daley
Lewy bodies and Lewy neurites composed primarily of α-synuclein characterize synucleinopathies including Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Despite decades of research on the impact of α-synuclein, little is known how abnormal inclusion made of this protein compromise neuronal function. Emerging evidence suggests that defects in axonal transport caused by aggregated α-synuclein contribute to neuronal dysfunction. These defects appear to occur well before the onset of neuronal death...
December 9, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27830778/defects-in-trafficking-bridge-parkinson-s-disease-pathology-and-genetics
#9
REVIEW
Asa Abeliovich, Aaron D Gitler
Parkinson's disease is a debilitating, age-associated movement disorder. A central aspect of the pathophysiology of Parkinson's disease is the progressive demise of midbrain dopamine neurons and their axonal projections, but the underlying causes of this loss are unclear. Advances in genetics and experimental model systems have illuminated an important role for defects in intracellular transport pathways to lysosomes. The accumulation of altered proteins and damaged mitochondria, particularly at axon terminals, ultimately might overwhelm the capacity of intracellular disposal mechanisms...
November 10, 2016: Nature
https://www.readbyqxmd.com/read/27757833/microtubule-destabilization-paves-the-way-to-parkinson-s-disease
#10
D Cartelli, G Cappelletti
Microtubules are dynamic structures normally associated to the cell division, during which they form the mitotic spindle, as well as to the initial phases of specification and polarization of various cell types, including neurons. Although microtubules could have a role in the death of many cells and tissues, the microtubule-based degenerative mechanisms have been poorly investigated; nevertheless, during the last two decades, many clues have been accumulated suggesting the importance of the microtubule system during neurodegeneration...
October 18, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27641766/mitochondrial-dynamics-in-visual-cortex-are-limited-in-vivo-and-not-affected-by-axonal-structural-plasticity
#11
Laura Smit-Rigter, Rajeev Rajendran, Catia A P Silva, Liselot Spierenburg, Femke Groeneweg, Emma M Ruimschotel, Danielle van Versendaal, Chris van der Togt, Ulf T Eysel, J Alexander Heimel, Christian Lohmann, Christiaan N Levelt
Mitochondria buffer intracellular Ca(2+) and provide energy [1]. Because synaptic structures with high Ca(2+) buffering [2-4] or energy demand [5] are often localized far away from the soma, mitochondria are actively transported to these sites [6-11]. Also, the removal and degradation of mitochondria are tightly regulated [9, 12, 13], because dysfunctional mitochondria are a source of reactive oxygen species, which can damage the cell [14]. Deficits in mitochondrial trafficking have been proposed to contribute to the pathogenesis of Parkinson's disease, schizophrenia, amyotrophic lateral sclerosis, optic atrophy, and Alzheimer's disease [13, 15-19]...
October 10, 2016: Current Biology: CB
https://www.readbyqxmd.com/read/27497486/is-axonal-degeneration-a-key-early-event-in-parkinson-s-disease
#12
Zuzanna Kurowska, Jeffrey H Kordower, A Jon Stoessl, Robert E Burke, Patrik Brundin, Zhenyu Yue, Scott T Brady, Jeffrey Milbrandt, Bruce D Trapp, Todd B Sherer, Satish Medicetty
Recent research suggests that in Parkinson's disease the long, thin and unmyelinated axons of dopaminergic neurons degenerate early in the disease process. We organized a workshop entitled 'Axonal Pathology in Parkinson's disease', on March 23rd, 2016, in Cleveland, Ohio with the goals of summarizing the state-of-the-art and defining key gaps in knowledge. A group of eight research leaders discussed new developments in clinical pathology, functional imaging, animal models, and mechanisms of degeneration including neuroinflammation, autophagy and axonal transport deficits...
October 19, 2016: Journal of Parkinson's Disease
https://www.readbyqxmd.com/read/27452482/live-imaging-of-mitochondrial-dynamics-in-cns-dopaminergic-neurons-in-vivo-demonstrates-early-reversal-of-mitochondrial-transport-following-mpp-exposure
#13
April A Dukes, Qing Bai, Victor S Van Laar, Yangzhong Zhou, Vladimir Ilin, Christopher N David, Zeynep S Agim, Joshua L Bonkowsky, Jason R Cannon, Simon C Watkins, Claudette M St Croix, Edward A Burton, Sarah B Berman
Extensive convergent evidence collectively suggests that mitochondrial dysfunction is central to the pathogenesis of Parkinson's disease (PD). Recently, changes in the dynamic properties of mitochondria have been increasingly implicated as a key proximate mechanism underlying neurodegeneration. However, studies have been limited by the lack of a model in which mitochondria can be imaged directly and dynamically in dopaminergic neurons of the intact vertebrate CNS. We generated transgenic zebrafish in which mitochondria of dopaminergic neurons are labeled with a fluorescent reporter, and optimized methods allowing direct intravital imaging of CNS dopaminergic axons and measurement of mitochondrial transport in vivo...
November 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27413149/compartmentalized-regulation-of-parkin-mediated-mitochondrial-quality-control-in-the-drosophila-nervous-system-in-vivo
#14
Hyun Sung, Lauren C Tandarich, Kenny Nguyen, Peter J Hollenbeck
UNLABELLED: In neurons, the normal distribution and selective removal of mitochondria are considered essential for maintaining the functions of the large asymmetric cell and its diverse compartments. Parkin, a E3 ubiquitin ligase associated with familial Parkinson's disease, has been implicated in mitochondrial dynamics and removal in cells including neurons. However, it is not clear how Parkin functions in mitochondrial turnover in vivo, or whether Parkin-dependent events of the mitochondrial life cycle occur in all neuronal compartments...
July 13, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27193205/early-synaptic-dysfunction-in-parkinson-s-disease-insights-from-animal-models
#15
REVIEW
Tommaso Schirinzi, Graziella Madeo, Giuseppina Martella, Marta Maltese, Barbara Picconi, Paolo Calabresi, Antonio Pisani
The appearance of motor manifestations in Parkinson's disease (PD) is invariably linked to degeneration of nigral dopaminergic neurons of the substantia nigra pars compacta. Traditional views on PD neuropathology have been grounded in the assumption that the prime event of neurodegeneration involves neuronal cell bodies with the accumulation of metabolic products. However, this view has recently been challenged by both clinical and experimental evidence. Neuropathological studies in human brain samples and both in vivo and in vitro models support the hypothesis that nigrostriatal synapses may indeed be affected at the earliest stages of the neurodegenerative process...
June 2016: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/27148685/distal-retinal-ganglion-cell-axon-transport-loss-and-activation-of-p38-mapk-stress-pathway-following-vegf-a-antagonism
#16
R Foxton, A Osborne, K R Martin, Y-S Ng, D T Shima
There is increasing evidence that VEGF-A antagonists may be detrimental to neuronal health following ocular administration. Here we investigated firstly the effects of VEGF-A neutralization on retinal neuronal survival in the Ins2(Akita) diabetic and JR5558 spontaneous choroidal neovascularization (CNV) mice, and then looked at potential mechanisms contributing to cell death. We detected elevated apoptosis in the ganglion cell layer in both these models following VEGF-A antagonism, indicating that even when vascular pathologies respond to treatment, neurons are still vulnerable to reduced VEGF-A levels...
May 5, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27095262/the-cytoskeleton-as-a-novel-therapeutic-target-for-old-neurodegenerative-disorders
#17
REVIEW
Jessica Eira, Catarina Santos Silva, Mónica Mendes Sousa, Márcia Almeida Liz
Cytoskeleton defects, including alterations in microtubule stability, in axonal transport as well as in actin dynamics, have been characterized in several unrelated neurodegenerative conditions. These observations suggest that defects of cytoskeleton organization may be a common feature contributing to neurodegeneration. In line with this hypothesis, drugs targeting the cytoskeleton are currently being tested in animal models and in human clinical trials, showing promising effects. Drugs that modulate microtubule stability, inhibitors of posttranslational modifications of cytoskeletal components, specifically compounds affecting the levels of tubulin acetylation, and compounds targeting signaling molecules which regulate cytoskeleton dynamics, constitute the mostly addressed therapeutic interventions aiming at preventing cytoskeleton damage in neurodegenerative disorders...
June 2016: Progress in Neurobiology
https://www.readbyqxmd.com/read/27078024/progressive-axonal-degeneration-of-nigrostriatal-dopaminergic-neurons-in-calcium-independent-phospholipase-a2%C3%AE-knockout-mice
#18
Goichi Beck, Koei Shinzawa, Hideki Hayakawa, Kousuke Baba, Hisae Sumi-Akamaru, Yoshihide Tsujimoto, Hideki Mochizuki
Calcium-independent phospholipase A2β (iPLA2β, PLA2G6) is essential for the remodeling of membrane glycerophospholipids. Mutations in this gene are responsible for autosomal recessive, young onset, L-dopa-responsive parkinsonism (PARK14), suggesting a neurodegenerative condition in the nigrostriatal dopaminergic system in patients with PLA2G6 mutations. We previously observed slowly progressive motor deficits in iPLA2β-knockout (KO) mice. To clarify whether a deficiency of iPLA2β leads to the degeneration of nigrostriatal dopaminergic neurons, we analyzed the striatum of iPLA2β-KO mice...
2016: PloS One
https://www.readbyqxmd.com/read/27014695/dietary-plant-lectins-appear-to-be-transported-from-the-gut-to-gain-access-to-and-alter-dopaminergic-neurons-of-caenorhabditis-elegans-a-potential-etiology-of-parkinson-s-disease
#19
Jolene Zheng, Mingming Wang, Wenqian Wei, Jeffrey N Keller, Binita Adhikari, Jason F King, Michael L King, Nan Peng, Roger A Laine
Lectins from dietary plants have been shown to enhance drug absorption in the gastrointestinal tract of rats, be transported trans-synaptically as shown by tracing of axonal and dendritic paths, and enhance gene delivery. Other carbohydrate-binding protein toxins are known to traverse the gut intact in dogs. Post-feeding rhodamine- or TRITC-tagged dietary lectins, the lectins were tracked from gut to dopaminergic neurons (DAergic-N) in transgenic Caenorhabditis elegans (C. elegans) [egIs1(Pdat-1:GFP)] where the mutant has the green fluorescent protein (GFP) gene fused to a dopamine transport protein gene labeling DAergic-N...
2016: Frontiers in Nutrition
https://www.readbyqxmd.com/read/27003787/alterations-in-activity-dependent-neuroprotective-protein-in-sporadic-and-experimental-parkinson-s-disease
#20
Yaping Chu, Gerardo A Morfini, Jeffrey H Kordower
BACKGROUND: Activity-dependent neuroprotective protein (ADNP) is essential for brain formation and neuronal survival. It is possible that intracellular alpha-synuclein (α-syn) inclusions may be due to, or may cause, down-regulation of ADNP expression. OBJECTIVE: This study were to determine whether ADNP protein levels are altered in nigral dopaminergic neurons, establish whether ADNP alterations are associated with α-syn accumulation, and evaluate potential correlations between levels of ADNP expression and axonal transport motor proteins in sporadic and experimental Parkinson's disease (PD)...
2016: Journal of Parkinson's Disease
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