Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).
In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
Multiple
Autophagy
2021
Journal Article
<table width="91" style="border-collapse:collapse;width:68pt;"><colgroup><col width="91" style="width:68pt;" /></colgroup><tbody><tr style="height:15pt;"><td width="91" height="20" class="xl18" style="width:68pt;height:15pt;"><a href="http://doi.org/10.1080/15548627.2020.1797280">http://doi.org/10.1080/15548627.2020.1797280</a></td>
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Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).
Autophagosome; cancer; flux; LC3; lysosome; macroautophagy; neurodegeneration; phagophore; stress; vacuole
In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
Autophagy
2021
2021-02-08
journalArticle
<a href="http://doi.org/10.1080/15548627.2020.1797280" target="_blank" rel="noreferrer noopener">10.1080/15548627.2020.1797280</a>
Ngp1-01, A Multi-targeted Polycyclic Cage Amine, Attenuates Brain Endothelial Cell Death In Iron Overload Conditions
activator; barrier; calcium channels; channels provide; intracerebral hemorrhage; Iron-overload; neurodegeneration; neurodegenerative disorders; neuroprotection; Neurosciences & Neurology; Nimodipine; parkinsons-disease; permeability; rat-brain; toxicity; transport; Vascular endothelial cells; Voltage-gated calcium channel
Development and progression of neurodegenerative disorders have, amongst other potential causes, been attributed to a disruption of iron regulatory mechanisms and iron accumulation. Excess extracellular iron may enter cells via nontraditional routes such as voltage-gated calcium channels and N-methyl-D-aspartate (NMDA) receptors leading to intracellular oxidative damage and ultimately mitochondrial failure. Nimodipine, an L-type calcium channel blocker has been shown to reduce iron-induced toxicity in neuronal and brain endothelial cells. Our current study investigates NGP1-01, a multimodal drug acting as an antagonist at both the NMDA receptor and the L-type calcium channel. Our previous studies support NGP1-01. as a promising neuroprotective agent in diseases involving calcium-related excitotoxicity. We demonstrate here that NGP1-01 (1 and 10 mu M) pretreatment abrogates the effects of iron overload in brain endothelial cells protecting cellular viability. Both concentrations of NGP1-01 were found to attenuate iron-induced reduction in cellular viability to a similar extent, and were statistically significant. To further verify the mechanism, the L-type calcium channel agonist FPL 64176 was administered to promote iron uptake. Addition of NGP1-01 dose-dependently reduced FPL 64176 stimulated uptake of iron. These data support further evaluation of NGP1-01 as a neuroprotective agent, not only in diseases associated with excitotoxicity, but also in those of iron overload. (C) 2012 Elsevier B.V. All rights reserved.
Lockman J A; Geldenhuys W J; Jones-Higgins M R; Patrick J D; Allen D D; Van der Schyf C J
Brain Research
2012
2012-12
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.brainres.2012.10.029" target="_blank" rel="noreferrer noopener">10.1016/j.brainres.2012.10.029</a>
Exome Sequencing Reveals A Novel Wdr45 Frameshift Mutation And Inherited Polr3a Heterozygous Variants In A Female With A Complex Phenotype And Mixed Brain Mri Findings
4H syndrome; accumulation; atp13a2 mutations; clinical spectrum; Demyelinating disease; diabetes-mellitus; gene; Genetics & Heredity; hallervorden-spatz-syndrome; hypogonadism; iron; Leukodystrophy; Leukodystrophy; NBIA; neurodegeneration; POLR3A; spastic paraplegia spg35; WDR45; Whole exome sequencing
WDR45 and POLR3A are newly recognized genes; each is associated with a distinct neurodegenerative disease. WDR45 is an X-linked gene associated with a dominant form of Neurodegeneration with Brain Iron Accumulation (NBIA), manifested by progressive disabilities, dystonia, cognitive decline, spastic paraplegia, neuropsychiatric abnormalities and iron deposition in the basal ganglia on brain imaging. POLR3A, on the other hand, is an autosomal gene, and its mutations cause a recessive form of a hypomyelination with leukodystrophy disease, also known as 4H syndrome, characterized by congenital Hypomyelination with thinning of the corpus callosum, Hypodontia and Hypogonadotropic Hypogonadism. We report on a female child with severe intellectual disability, aphasia, short stature, ataxia, failure to thrive and structural brain abnormalities. Brain MRI obtained in late infancy showed hypomyelination involving the central periventricular white matter and thinning of the corpus callosum with no evidence of iron accumulation. Brain MRI obtained in childhood showed stable hypomyelination, with progressive iron accumulation in the basal ganglia, in particular in the globus pallidus and substantia nigra. Whole Exome Sequencing (WES) identified a novel WDR45 frameshift deleterious mutation in Exon 9 (c.587-588del) and also revealed three POLR3A missense heterozygous variants. The first is a maternally inherited novel missense variant in exon 4 (c.346A > G). Exon 13 carried two heterozygous missense variants, a maternally inherited variant (c.1724A > T) and a paternally inherited variant (1745G > A). These variants are considered likely damaging. The patient's complex clinical phenotype and mixed brain MRI findings might be attributed to the confounding effects of the expression of these two mutant genes. (C) 2015 Elsevier Masson SAS. All rights reserved.
Khalifa M; Naffaa L
European Journal of Medical Genetics
2015
2015-08
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.ejmg.2015.05.009" target="_blank" rel="noreferrer noopener">10.1016/j.ejmg.2015.05.009</a>
Molecular Insights Into Human Monoamine Oxidase B Inhibition By The Glitazone Antidiabetes Drugs
Antidiabetes drug; Chemistry; drug design; gamma agonist pioglitazone; high-level expression; lsd1; monoamine oxidase; mouse model; neurodegeneration; neuroprotection; parkinsons-disease; parkinsons-disease; Pharmacology & Pharmacy; pichia-pastoris; pioglitazone; rosiglitazone
The widely employed antidiabetic drug pioglitazone (Actos) is shown to be a specific and reversible inhibitor of human monoamine oxidase B (MAO B). The crystal structure of the enzyme-inhibitor complex shows that the R-enantiomer is bound with the thiazolidinedione ring near the flavin. The molecule occupies both substrate and entrance cavities of the active site, establishing noncovalent interactions with the surrounding amino acids. These binding properties differentiate pioglitazone from the clinically used MAO inhibitors, which act through covalent inhibition mechanisms and do not exhibit a high degree of MAO A versus B selectivity. Rosiglitazone (Avandia) and troglitazone, other members of the glitazone class, are less selective in that they are weaker inhibitors of both MAO A and MAO B. These results suggest that pioglitazone may have utility as a "repurposed" neuroprotectant drug in retarding the progression of disease in Parkinson's patients. They also provide new insights for the development of reversible isoenzyme-specific MAO inhibitors.
Binda C; Aldeco M; Geldenhuys W J; Tortorici M; Mattevi A; Edmondson D E
Acs Medicinal Chemistry Letters
2012
2012-01
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1021/ml200196p" target="_blank" rel="noreferrer noopener">10.1021/ml200196p</a>
Brain Iron Toxicity: Differential Responses Of Astrocytes, Neurons, And Endothelial Cells
astrocyte; Biochemistry & Molecular Biology; brain iron toxicity; central-nervous-system; cerebrospinal-fluid; endothelial cell; experimental intracerebral hemorrhage; low-molecular-weight; multifunctional neuroprotective drugs; neurodegeneration; neuron; Neurosciences & Neurology; oxidative stress; parkinsons-disease; protein messenger-rna; receptor-mediated transcytosis; toxic mechanisms; transferrin receptor
Gaasch J A; Lockman P R; Geldenhuys W J; Allen D D; Van der Schyf C J
Neurochemical Research
2007
2007-07
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1007/s11064-007-9290-4" target="_blank" rel="noreferrer noopener">10.1007/s11064-007-9290-4</a>
Voltage-gated Calcium Channels Provide An Alternate Route For Iron Uptake In Neuronal Cell Cultures
alzheimer-disease; alzheimers-disease; Biochemistry & Molecular Biology; fpl-64176; iron-overload toxicity; metabolism; mouse-brain; nerve growth-factor; neuroblastoma-cells; neurodegeneration; Neurosciences & Neurology; nimodipine; parkinsons-disease; parkinsons-disease; redox-active iron; substantia nigra; transferrin receptor; voltage-gated calcium channels
Gaasch J A; Geldenhuys W J; Lockman P R; Allen D D; Van der Schyf C J
Neurochemical Research
2007
2007-10
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1007/s11064-007-9313-1" target="_blank" rel="noreferrer noopener">10.1007/s11064-007-9313-1</a>
Estrogen, Testosterone, And Methamphetamine Toxicity
17-beta-estradiol; c57/b1 mice; differences; female; gonadal steroids; inhibition; mptp-induced neurotoxicity; neurodegeneration; neuroprotection; neurotoxicity; nigrostriatal; nigrostriatal dopaminergic system; parkinsons-disease; sex; sexual differences; striatum; tamoxifen
Dluzen D E; McDermott J L
Cellular and Molecular Mechanisms of Drugs of Abuse and Neurotoxicity: Cocaine, Ghb, and Substituted Amphetamines
2006
2006
Book Chapter
n/a
Developmental And Genetic Influences Upon Gender Differences In Methamphetamine-induced Nigrostriatal Dopaminergic Neurotoxicity
bdnf mutant mice; brain; brain-derived neurotrophic factor (BDNF); differentiation; dopamine; estrogen; female mice; gonadal-hormones; messenger-rna; mptp-induced neurotoxicity; neurodegeneration; neuroprotection; neurotrophic factor; parkinsons-disease; sexual; sexual differences; testosterone; ventral mesencephalon
Dluzen D E; McDermott J L
Current Status of Drug Dependence / Abuse Studies: Cellular and Molecular Mechanisms of Drugs of Abuse and Neurotoxicity
2004
2004
Book Chapter
n/a
Abnormal Metal Levels In The Primary Visual Pathway Of The Dba/2j Mouse Model Of Glaucoma
alzheimers-disease; amyloid-beta; aqueous-humor; Biochemistry & Molecular Biology; ganglion-cell degeneration; gene-expression; Glaucoma; ICP-MS; iron; microarray analysis; neurodegeneration; neurodegeneration; Retina; Retina; Superior colliculus; synapse
DeToma A S; Dengler-Crish C M; Deb A; Braymer J J; Penner-Hahn J E; Van der Schyf C J; Lim M H; Crish S D
Biometals
2014
2014-12
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1007/s10534-014-9790-z" target="_blank" rel="noreferrer noopener">10.1007/s10534-014-9790-z</a>
Molecular Insights Into Human Monoamine Oxidase B Inhibition By The Glitazone Antidiabetes Drugs
Antidiabetes drug; Chemistry; drug design; gamma agonist pioglitazone; high-level expression; lsd1; monoamine oxidase; mouse model; neurodegeneration; neuroprotection; parkinsons-disease; parkinsons-disease; Pharmacology & Pharmacy; pichia-pastoris; pioglitazone; rosiglitazone
Binda C; Aldeco M; Geldenhuys W J; Tortorici M; Mattevi A; Edmondson D E
Acs Medicinal Chemistry Letters
2012
2012-01
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1021/ml200196p" target="_blank" rel="noreferrer noopener">10.1021/ml200196p</a>
Proximal inhibition of p38 MAPK stress signaling prevents distal axonopathy
Glaucoma; Neurodegeneration; Neurosciences & Neurology; death; amyotrophic-lateral-sclerosis; mouse model; ocular hypertension; activated protein-kinase; up-regulation; alzheimers-disease brain; Axonopathy; experimental glaucoma; ganglion-cell neurons; Heat shock protein; p38 MAPK; rat retina; Retinal ganglion cell
The p38 mitogen-activated protein kinase (MAPK) isoforms are phosphorylated by a variety of stress stimuli in neurodegenerative disease and act as upstream activators of myriad pathogenic processes. Thus, p38 MAPK inhibitors are of growing interest as possible therapeutic interventions. Axonal dysfunction is an early component of most neurodegenerative disorders, including the most prevalent optic neuropathy, glaucoma. Sensitivity to intraocular pressure at an early stage disrupts anterograde transport along retinal ganglion cell (RGC) axons to projection targets in the brain with subsequent degeneration of the axons themselves; RGC body loss is much later. Here we show that elevated ocular pressure in rats increases p38 MAPK activation in retina, especially in RGC bodies. Topical eye-drop application of a potent and selective inhibitor of the p38 MAPK catalytic domain (Ro3206145) prevented both the degradation of anterograde transport to the brain and degeneration of axons in the optic nerve. Ro3206145 reduced in the retina phosphorylation of tau and heat-shock protein 27, both down-stream targets of p38 IVIAPK activation implicated in glaucoma, as well as expression of two inflammatory responses. We also observed increased p38 MAPK activation in mouse models. Thus, inhibition of p38 MAPK signaling in the retina may represent a therapeutic target for preventing early pathogenesis in optic neuropathies. (C) 2013 Elsevier Inc. All rights reserved.
Dapper J D; Crish S D; Pang I H; Calkins D J
Neurobiology of Disease
2013
2013-11
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.nbd.2013.07.001" target="_blank" rel="noreferrer noopener">10.1016/j.nbd.2013.07.001</a>
Early pro-inflammatory cytokine elevations in the DBA/2J mouse model of glaucoma
Aging; axonal-transport; axoplasmic-transport; Cytokines; fibroblast-growth-factor; gene-expression; glaucoma; Immunology; inflammation; Intraocular pressure; Intraocular pressure; necrosis-factor-alpha; neurodegeneration; Neurosciences & Neurology; ocular hypertension; optic-nerve head; retinal ganglion-cells; tnf-alpha
Background: Neuroinflammation-astrogliosis, microglial activation, and changes in cytokine signaling-is a prominent feature of neurodegenerative disorders. Glaucoma is a group of chronic neurodegenerative conditions that make up the leading cause of irreversible blindness worldwide. Neuroinflammation has been postulated to play a significant role in the pathogenesis and progression of glaucomatous neurodegeneration. Though much is known regarding inflammation in the eye in glaucoma, little is known about cytokine activity outside of the retina where pathologies develop early. Methods: We traced the primary visual projection from the eye to the superior colliculus (SC) in DBA/2J and DBA/2J. Gpnmb(+) (control) mice using the anterograde tracer cholera toxin-B (CTB) to assay axonal transport deficits. Forty-eight hours later, visual structures were microdissected from fresh tissue based on transport outcome. Using magnetic bead multiplexing assays, we measured levels of 20 cytokines in the retina, proximal and distal optic nerves, CTB-positive and negative SC subdivisions, cerebellum, and serum at different ages representing different stages of pathology. Results: Pro-and anti-inflammatory cytokine levels in mice often changed in the same direction based on strain, age, and tissue. Significant elevations in retinal pro-inflammatory cytokines were observed in young DBA/2J mice compared to controls, followed by an age-dependent decrease in the DBA/2J mice. Proximal optic nerve of young DBA/2J mice showed a 50 % or greater decrease in levels of certain cytokines compared to older DBA/2J cohorts and controls, while both proximal and distal optic nerve of DBA/2Js showed elevations in IL-1 beta at all ages compared to controls. Pro-inflammatory cytokine IL-6 levels varied in accordance with transport outcome in the SC: IL-6 was elevated 44-80 % in glaucomatous DBA/2J collicular regions deficient in anterograde transport from retinal ganglion cells (RGCs) compared to areas with intact transport. Conclusion: Dysregulation of cytokine signaling in the RGC projection of DBA/2J mice was evident early in distal retinal targets, well before intraocular pressure elevation or axonal degeneration begins.
Wilson G N; Inman D M; Denger-Crish C M; Smith M A; Crish S D
Journal of Neuroinflammation
2015
2015-09
Journal Article
<a href="http://doi.org/10.1186/s12974-015-0399-0" target="_blank" rel="noreferrer noopener">10.1186/s12974-015-0399-0</a>
Dissecting the determinants of neuropathogenesis of the murine oncornaviruses
c rna virus; central-nervous-system; endothelial-cell tropism; induced spongiform; infection; leukemia-virus; motor neuron disease; neurodegeneration; neurological disease; neurotropic retrovirus; temperature-sensitive mutant; Virology; wild mouse retrovirus
Portis J L; Lynch W P
Virology
1998
1998-08
Journal Article
<a href="http://doi.org/10.1006/viro.1998.9240" target="_blank" rel="noreferrer noopener">10.1006/viro.1998.9240</a>
Cross-Talk Between Stem Cells and the Dysfunctional Brain is Facilitated by Manipulating the Niche: Evidence from an Adhesion Molecule
adhesion molecule; Aging; aging and age-related diseases; astrocytes; axonal regeneration; Biotechnology & Applied Microbiology; Cell Biology; central-nervous-system; chaperone effect; differentiation; dopamine; extracellular; functional recovery; Hematology; L1; matrix; migration; model; molecules; motor-neurons; mouse; MPTP; neural stem cells; neurodegeneration; neuroprotection; neurotrophic factors; niche; Oncology; oxidative stress; parkinsons-disease; parkinsons-disease; protect neurons; recognition; spinal-cord-injury; transplantation
In the injured brain, the behavior of neural stem/progenitor cells (NSCs) is regulated by multiple converging factors encountered in the niche, which is composed of several neural and non-neural cell types. Signals emanating from the host influence the migration, survival, distribution, and fate of transplanted NSCs, which in turn can create host microenvironments that favor a return to homeostasis. We tested the hypothesis that overexpression of key facilitatory molecules that de. ne the injury niche might enhance this bidirectional stem cell host interaction to therapeutic advantage. As proof of concept, we investigated whether conditioning the niche with the neural cell adhesion molecule L1 might enhance recovery in a prototypical neurodegenerative milieu-the MPTP-induced model of Parkinson's disease in aged mice-where cross-talk between NSCs and imperiled host dopaminergic neurons is known to be pivotal in rescuing the function and connectivity of the latter. In lesioned mice (and in unlesioned controls), we overexpressed L1 in the NSCs to be transplanted into the ventral mesencephalon. Several pairwise experimental combinations were tested based on variations of engrafting L1 overexpressing versus nonoverexpressing NSCs into wild-type (WT) versus L1-overexpressing transgenic mice (specifically L1 transcribed from the GFAP promoter and, hence, overexpressed in host astrocytes). Enrichment for L1-particularly when expressed simultaneously in both donor NSCs and host brain-led to rapid and extensive distribution of exogenous NSCs, which in turn rescued (with an efficacy greater than in nonengineered controls) dysfunctional host dopaminergic nigral neurons, even when grafting was delayed by a month. L1 overexpression by NSCs also enhanced their own differentiation into tyrosine hydroxylase-expressing neurons in both WT and transgenic hosts. Graft-host interactions were thus favored by progressively increasing levels of L1. More broadly, this study supports the view that manipulating components of the niche (such as an adhesion molecule) that facilitate cross-talk between stem cells and the dysfunctional brain may offer new strategies for more efficacious neurotransplantation, particularly when treatment is delayed as in chronic lesions or advanced stages of a neurodegenerative disease. STEM CELLS 2009; 27: 2846-2856
Ourednik V; Ourednik J; Xu Y F; Zhang Y; Lynch W P; Snyder E Y; Schachner M
Stem Cells
2009
2009-11
Journal Article
<a href="http://doi.org/10.1002/stem.227" target="_blank" rel="noreferrer noopener">10.1002/stem.227</a>
Neurotoxicity of pesticides.
activity; cell-culture; developmental; Dichlorodiphenyltrichloroethane; Dieldrin; Endosulfan; exposure; Fungicide; Glyphosate; glyphosate-based herbicide; induced oxidative stress; iPSC; Microelectrode array; Mitochondrial Complex I; mitochondrial complex-i; Neurodegeneration; neuronal network; Neurosciences & Neurology; Neurotoxicity; Neurotoxicity; nigrostriatal dopamine system; Organochlorine; Organophosphate; Paraquat; parkinsons-disease; Pathology; Pesticide; Pyrethroid; pyrethroid insecticides; Pyridaben; reproduces features; Rotenone; Zebrafish
Pesticides are unique environmental contaminants that are specifically introduced into the environment to control pests, often by killing them. Although pesticide application serves many important purposes, including protection against crop loss and against vector-borne diseases, there are significant concerns over the potential toxic effects of pesticides to non-target organisms, including humans. In many cases, the molecular target of a pesticide is shared by non-target species, leading to the potential for untoward effects. Here, we review the history of pesticide usage and the neurotoxicity of selected classes of pesticides, including insecticides, herbicides, and fungicides, to humans and experimental animals. Specific emphasis is given to linkages between exposure to pesticides and risk of neurological disease and dysfunction in humans coupled with mechanistic findings in humans and animal models. Finally, we discuss emerging techniques and strategies to improve translation from animal models to humans. [ABSTRACT FROM AUTHOR]
Richardson Jason R; Fitsanakis Vanessa; Westerink Remco H S; Kanthasamy Anumantha G
Acta Neuropathologica
2019
2019-09
<a href="http://doi.org/10.1007/s00401-019-02033-9" target="_blank" rel="noreferrer noopener">10.1007/s00401-019-02033-9</a>
Neurotoxicity of pesticides
Dichlorodiphenyltrichloroethane; Dieldrin; Endosulfan; Fungicide; Glyphosate; iPSC; Microelectrode array; Mitochondrial Complex I; Neurodegeneration; Neurotoxicity; Organochlorine; Organophosphate; Paraquat; Pesticide; Pyrethroid; Pyridaben; Rotenone; Zebrafish
Pesticides are unique environmental contaminants that are specifically introduced into the environment to control pests, often by killing them. Although pesticide application serves many important purposes, including protection against crop loss and against vector-borne diseases, there are significant concerns over the potential toxic effects of pesticides to non-target organisms, including humans. In many cases, the molecular target of a pesticide is shared by non-target species, leading to the potential for untoward effects. Here, we review the history of pesticide usage and the neurotoxicity of selected classes of pesticides, including insecticides, herbicides, and fungicides, to humans and experimental animals. Specific emphasis is given to linkages between exposure to pesticides and risk of neurological disease and dysfunction in humans coupled with mechanistic findings in humans and animal models. Finally, we discuss emerging techniques and strategies to improve translation from animal models to humans.
Richardson Jason R; Fitsanakis Vanessa; Westerink Remco H S; Kanthasamy Anumantha G
Acta Neuropathologica
2019
2019-06
<a href="http://doi.org/10.1007/s00401-019-02033-9" target="_blank" rel="noreferrer noopener">10.1007/s00401-019-02033-9</a>
Anterograde transport blockade precedes deficits in retrograde transport in the visual projection of the DBA/2J mouse model of glaucoma.
glaucoma; optic nerve; axonal transport; axonopathy; neurodegeneration; ocular; superior colliculi; vision disorders
Axonal transport deficits have been reported as an early pathology in several neurodegenerative disorders, including glaucoma. However, the progression and mechanisms of these deficits are poorly understood. Previous work suggests that anterograde transport is affected earlier and to a larger degree than retrograde transport, yet this has never been examined directly in vivo. Using combined anterograde and retrograde tract tracing methods, we examined the time-course of anterograde and retrograde transport deficits in the retinofugal projection in pre-glaucomatous (3 month-old) and glaucomatous (9-13 month old) DBA/2J mice. DBA/2J-Gpnmb (+) mice were used as a control strain and were shown to have similar retinal ganglion cell densities as C57BL/6J control mice-a strain commonly investigated in the field of vision research. Using cholera toxin-B injections into the eye and FluoroGold injections into the superior colliculus (SC), we were able to measure anterograde and retrograde transport in the primary visual projection. In DBA/2J, anterograde transport from the retina to SC was decreased by 69% in the 9-10 month-old age group, while retrograde transport was only reduced by 23% from levels seen in pre-glaucomatous mice. Despite this minor reduction, retrograde transport remained largely intact in these glaucomatous age groups until 13-months of age. These findings indicate that axonal transport deficits occur in semi-functional axons that are still connected to their brain targets. Structural persistence as determined by presence of estrogen-related receptor beta label in the superficial SC was maintained beyond time-points where reductions in retrograde transport occurred, also supporting that transport deficits may be due to physiological or functional abnormalities as opposed to overt structural loss.
Dengler-Crish Christine M; Smith Matthew A; Inman Denise M; Wilson Gina N; Young Jesse W; Crish Samuel D
Frontiers in neuroscience
2014
1905-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.3389/fnins.2014.00290" target="_blank" rel="noreferrer noopener">10.3389/fnins.2014.00290</a>
Glycoprotein NMB: an Emerging Role in Neurodegenerative Disease.
Animals; GPNMB; Humans; Immune System/metabolism; Membrane Glycoproteins/chemistry/*metabolism; Nerve Degeneration/pathology; Neurodegeneration; Neurodegenerative Diseases/*metabolism/therapy; Neuroinflammation; Neuroprotection
Neurodegeneration is characterized by severe neuronal loss leading to the cognitive and physical impairments that define various neurodegenerative diseases. Neuroinflammation is one hallmark of neurodegenerative diseases and can ultimately contribute to disease progression. Increased inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-1beta (IL-1 beta), and tumor necrosis factor-alpha (TNF-alpha) are associated with Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Unfortunately, current therapeutic options lack ability to stop or effectively slow progression of these diseases and are primarily aimed at alleviating symptoms. Thus, it is crucial to discover novel treatment candidates for neurodegenerative diseases. Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type-I transmembrane glycoprotein first identified in a melanoma cell line. GPNMB augments bone mineral deposition by stimulating osteoblast differentiation. Aside from its anabolic function in the bone, emerging evidence suggests that GPNMB has anti-inflammatory and reparative functions. GPNMB has also been demonstrated to be neuroprotective in an animal model of ALS, cerebral ischemia, and other disease models. Given these discoveries, GPNMB should be investigated as a potential therapeutic option for multiple neurodegenerative diseases.
Budge Kevin M; Neal Matthew L; Richardson Jason R; Safadi Fayez F
Molecular neurobiology
2018
2018-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1007/s12035-017-0707-z" target="_blank" rel="noreferrer noopener">10.1007/s12035-017-0707-z</a>
Synthesis and Biological Evaluation of Pentacycloundecylamines and Triquinylamines as Voltage-Gated Calcium Channel Blockers.
Alicyclic/chemical synthesis/*chemistry/pharmacology; Amines/chemical synthesis/*chemistry/pharmacology; Animals; Apoptosis/drug effects; Calcium Channel Blockers/chemical synthesis/*chemistry/pharmacology; Calcium Channels; Calcium/*metabolism; Cell Survival/drug effects; Hydrocarbons; Hydrogen Peroxide/pharmacology; L-Lactate Dehydrogenase/metabolism; L-type calcium channel (LTCC) blockers; L-Type/*metabolism; Multifunctional drugs; Neurodegeneration; PC12 Cells; Pentacycloundecylamine; Quinones/chemical synthesis/*chemistry/pharmacology; Rats; Structure-Activity Relationship; Triquinylamine
Preclinical studies for neurodegenerative diseases have shown a multi-targeted approach to be successful in the treatment of these complex disorders with several pathoetiological pathways. Polycyclic compounds, such as NGP1-01 (7a), have demonstrated the ability to target multiple mechanisms of the complex etiology and are referred to as multifunctional compounds. These compounds have served as scaffolds with the ability to attenuate Ca(2+) overload and excitotoxicity through several pathways. In this study, our focus was on mitigating Ca(2+) overload through the L-type calcium channels (LTCC). Here, we report the synthesis and biological evaluation of several novel polycyclic compounds. We determined the IC50 values for both the pentacycloundecylamines and the triquinylamines by means of a high-throughput fluorescence calcium flux assay utilizing Fura-2/AM. The potential of these compounds to offer protection against hydrogen peroxide-induced cell death was also evaluated. Overall,
Young Lois-May; Geldenhuys Werner J; Domingo Olwen C; Malan Sarel F; Van der Schyf Cornelis J
Archiv der Pharmazie
2016
2016-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/ardp.201500293" target="_blank" rel="noreferrer noopener">10.1002/ardp.201500293</a>