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axon transport parkinso*

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 9, 2016: Nature
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
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
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
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
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
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
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...
2016: Cell Death & Disease
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
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
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
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
Ling-Bo Li, Haoyun Lei, Rachel N Arey, Pengpeng Li, Jianfeng Liu, Coleen T Murphy, X Z Shawn Xu, Kang Shen
Aging is the greatest risk factor for a number of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Furthermore, normal aging is associated with a decline in sensory, motor, and cognitive functions. Emerging evidence suggests that synapse alterations, rather than neuronal cell death, are the causes of neuronal dysfunctions in normal aging and in early stages of neurodegenerative diseases. However, little is known about the mechanisms underlying age-related synaptic decline. Here, we uncover a surprising role of the anterograde molecular motor UNC-104/KIF1A as a key regulator of neural circuit deterioration in aging C...
March 7, 2016: Current Biology: CB
Takashi Fukuzono, Strahil Iv Pastuhov, Okinobu Fukushima, Chun Li, Ayuna Hattori, Shun-ichiro Iemura, Tohru Natsume, Hiroshi Shibuya, Hiroshi Hanafusa, Kunihiro Matsumoto, Naoki Hisamoto
Mutations in LRRK2 are linked to autosomal dominant forms of Parkinson's disease. We identified two human proteins that bind to LRRK2: BAG2 and HSC70, which are known to form a chaperone complex. We characterized the role of their Caenorhabditis elegans homologues, UNC-23 and HSP-1, in the regulation of LRK-1, the sole homologue of human LRRK2. In C. elegans, LRK-1 determines the polarized sorting of synaptic vesicle (SV) proteins to the axons by excluding SV proteins from the dendrite-specific transport machinery in the Golgi...
April 2016: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Massimiliano Gasparrini, Francesca Giampieri, Josè Alvarez Suarez, Luca Mazzoni, Tamara Y Forbes Hernandez, Josè L Quiles, Pedro Bullon, Maurizio Battino
AMPK is a serine/threonine protein kinase that has the function of maintaining the balance between ATP production and consumption in most eukaryotic cells. It plays a relevant role in regulating cellular metabolism, preserving cellular energy homeostasis, and is involved in many other cellular processes as well as metabolic ones, including cell cycle regulation and endothelial and vascular relaxation. Recently, the effects of naturally occurring compounds able to prevent and treat diseases through AMPK activation have attracted the attention of many researchers...
2016: Current Drug Targets
Michel Brahic, Luc Bousset, Gregor Bieri, Ronald Melki, Aaron D Gitler
Accruing evidence suggests that prion-like behavior of fibrillar forms of α-synuclein, β-amyloid peptide and mutant huntingtin are responsible for the spread of the lesions that characterize Parkinson disease, Alzheimer disease and Huntington disease, respectively. It is unknown whether these distinct protein assemblies are transported within and between neurons by similar or distinct mechanisms. It is also unclear if neuronal death or injury is required for neuron-to-neuron transfer. To address these questions, we used mouse primary cortical neurons grown in microfluidic devices to measure the amounts of α-synuclein, Aβ42 and HTTExon1 fibrils transported by axons in both directions (anterograde and retrograde), as well as to examine the mechanism of their release from axons after anterograde transport...
April 2016: Acta Neuropathologica
Martin Reznitsky, Per Plenge, Anders Hay-Schmidt
The objective of this study is to establish which subdivision of the dorsal raphe nucleus (DRN) supplies serotonergic projections to the subthalamic nucleus (STN) in the rat brain. Several studies in recent years have shown that serotonin (5-HT) might have a therapeutic role in the most prevalent basal ganglia (BG) movement disorder, Parkinson's disease (PD), but, because of the depletion of dopaminergic input to the BG, l-DOPA has been the main treatment for PD patients. Autoradiography showed that serotonin receptors 5-HT1B and 5-HT2C and the serotonin transporter were present in STN, whereas the 5-HT1A and 5-HT2A not were present...
January 26, 2016: Neuroscience Letters
Margherita Grasso, Paola Piscopo, Alessio Crestini, Annamaria Confaloni, Michela A Denti
Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are caused by a combination of events that impair normal neuronal function. Although they are considered different disorders, there are overlapping features among them from the clinical, pathological, and genetic points of view. Synaptic dysfunction and loss, neurite retraction, and the appearance of other abnormalities such as axonal transport defects normally precede the neuronal loss that is a relatively late event...
2015: EXS
J-J Hauw, S Haïk, C Duyckaerts
Protein misfolding and spreading ("transconformation") are being better understood. Described in Prions diseases, this new paradigm in the field of neurodegenerative disorders and brain aging also implies sporadic inclusion myositis, type 2 diabetes, some cancers, sickle cell disease... Misfolding is transmitted from a protein or peptide to a normally folded one. Often associated with a stress of the endoplasmic reticulum, it may spread along the neurites, following anterograde or retrograde axonal transport...
December 2015: Revue Neurologique
Shao-Ju Weng, I-Hsun Li, Yuahn-Sieh Huang, Sheau-Huei Chueh, Ta-Kai Chou, San-Yuan Huang, Chyng-Yann Shiue, Cheng-Yi Cheng, Kuo-Hsing Ma
The pathology of Parkinson's disease (PD) results mainly from nigrostriatal pathway damage. Unfortunately, commonly used PD therapies do not repair the disconnected circuitry. It has been reported that using kainic acid (KA, an excitatory amino acid) in bridging transplantation may be useful to generate an artificial tract and reconstruct the nigrostriatal pathway in 6-hydroxydopamine (6-OHDA) lesioned rats. In this study, we used KA bridging and a co-graft of rat olfactory ensheathing cells (OECs) and rat E14 embryonic ventral mesencephalic (VM) tissue to restore the nigrostriatal pathway of the PD model rats...
October 29, 2015: Journal of Tissue Engineering and Regenerative Medicine
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