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  • 1
    Online Resource
    Online Resource
    Use of catechol- O -methyltransferase inhibition to minimize L-3,4-dihydroxyphenylalanine-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque
    Wiley ; 2013
    In:  European Journal of Neuroscience Vol. 37, No. 5 ( 2013-03), p. 831-838
    Details
    In: European Journal of Neuroscience, Wiley, Vol. 37, No. 5 ( 2013-03), p. 831-838
    Type of Medium: Online Resource
    ISSN: 0953-816X
    URL: Article
    DOI: 10.1111/ejn.12093
    Language: English
    Publisher: Wiley
    Publication Date: 2013
    detail.hit.zdb_id: 2005178-5
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Nigrostriatal Dysfunction in Familial Alzheimer's Disease-Linked APPswe/PS1ΔE9 Transgenic Mice
    Society for Neuroscience ; 2005
    In:  The Journal of Neuroscience Vol. 25, No. 44 ( 2005-11-02), p. 10220-10229
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 25, No. 44 ( 2005-11-02), p. 10220-10229
    Abstract: Alzheimer's disease (AD) is often accompanied by extrapyramidal signs attributed to nigrostriatal dysfunction. The association between amyloid deposition and nigrostriatal degeneration is essentially unknown. We showed previously that the striatum and the substantia nigra of transgenic mice harboring familial AD (FAD)-linked APPswe/PS1ΔE9 mutants exhibit morphological alterations accompanied by amyloid-β (Aβ) deposition (Perez et al., 2004). In the present study, we further investigated the interaction between Aβ deposition and dopaminergic nigrostriatal dysfunction, by correlating morphological and biochemical changes in the nigrostriatal pathway with amyloid deposition pathology in the brains of 3- to 17-month-old APPswe/PS1ΔE9 transgenic mice and age-matched wild-type controls. We show that Aβ deposition is pronounced in the striatum of APPswe/PS1ΔE9 mice at 6 months of age, and the extent of deposition increases in an age-dependent manner. Tyrosine hydroxylase (TH)-positive dystrophic neurites with rosette or grape-like cluster disposition are observed adjacent to Aβ plaques and display multilaminar, multivesicular, and dense-core bodies as well as mitochondria. In addition, an age-dependent increase of TH protein levels are shown in nigral cells in these mutant mice. Using HPLC analysis, we found a reduction in the dopamine metabolite DOPAC in the striatum of these mice. These findings show a close association between amyloid deposition and nigrostriatal pathology and suggest that altered FAD-linked amyloid metabolism impairs, at least in part, the function of dopaminergic neurons.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.2773-05.2005
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2005
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 3
    Online Resource
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    The Toll-Like Receptor-3 Agonist Polyinosinic:Polycytidylic Acid Triggers Nigrostriatal Dopaminergic Degeneration
    Society for Neuroscience ; 2010
    In:  The Journal of Neuroscience Vol. 30, No. 48 ( 2010-12-01), p. 16091-16101
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 30, No. 48 ( 2010-12-01), p. 16091-16101
    Abstract: In Parkinson's disease (PD), loss of striatal dopaminergic (DA) terminals and degeneration of DA neurons in the substantia nigra (SN) are associated with glial reactions. Such inflammatory processes are commonly considered an epiphenomenon of neuronal degeneration. However, there is increasing recognition of the role of neuroinflammation as an initiation factor of DA neuron degeneration. To investigate this issue, we established a new model of brain inflammation by injecting the Toll-like receptor 3 (TLR-3) agonist polyinosinic:polycytidylic acid [poly(I:C)] in the SN of adult rats. Poly(I:C) injection induced a sustained inflammatory reaction in the SN and in the dorsolateral striatum. Significant changes were detected in proteins relevant to synaptic transmission and axonal transport. In addition, cytoplasmic mislocalization of neuronal TAR DNA binding protein TDP-43 was observed. Poly(I:C) injection increased the susceptibility of midbrain DA neurons to a subsequent neurotoxic trigger (low-dose 6-hydroxydopamine). Systemic delivery of interleukin-1 receptor antagonist protected SN DA neurons exposed to combined poly(I:C) induced inflammatory and neurotoxic oxidative stress. These data indicate that viral-like neuroinflammation induces predegenerative changes in the DA system, which lowers the set point toward neuronal dysfunction and degeneration. New powerful neuroprotective therapies for PD might be considered by targeting critical inflammatory mechanisms, including cytokine-induced neurotoxicity.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.2400-10.2010
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2010
    detail.hit.zdb_id: 1475274-8
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  • 4
    Online Resource
    Online Resource
    Expression of human A53T alpha-synuclein in the rat substantia nigra using a novel AAV1/2 vector produces a rapidly evolving pathology with protein aggregation, dystrophic neurite architecture and nigrostriatal degeneration with potential to model the pathology of Parkinson's disease
    Springer Science and Business Media LLC ; 2010
    In:  Molecular Neurodegeneration Vol. 5, No. 1 ( 2010), p. 43-
    Details
    In: Molecular Neurodegeneration, Springer Science and Business Media LLC, Vol. 5, No. 1 ( 2010), p. 43-
    Type of Medium: Online Resource
    ISSN: 1750-1326
    URL: Article
    DOI: 10.1186/1750-1326-5-43
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2010
    detail.hit.zdb_id: 2244557-2
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  • 5
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    Functional enhancement and protection of dopaminergic terminals by RAB3B overexpression
    Proceedings of the National Academy of Sciences ; 2009
    In:  Proceedings of the National Academy of Sciences Vol. 106, No. 52 ( 2009-12-29), p. 22474-22479
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 106, No. 52 ( 2009-12-29), p. 22474-22479
    Abstract: In Parkinson's disease (PD), dopaminergic (DA) neurons in the substantia nigra (SN, A9) are particularly vulnerable, compared to adjacent DA neurons within the ventral tegmental area (VTA, A10). Here, we show that in rat and human, one RAB3 isoform, RAB3B, has higher expression levels in A10 compared to A9 neurons. RAB3 is a monomeric GTPase protein that is highly enriched in synaptic vesicles and is involved in synaptic vesicle trafficking and synaptic transmission, disturbances of which have been implicated in several neurodegenerative diseases, including PD. These findings prompted us to further investigate the biology and neuroprotective capacity of RAB3B both in vitro and in vivo. RAB3B overexpression in human dopaminergic BE (2)-M17 cells increased neurotransmitter content, [ 3 H] dopamine uptake, and levels of presynaptic proteins. AAV-mediated RAB3B overexpression in A9 DA neurons of the rat SN increased striatal dopamine content, number and size of synaptic vesicles, and levels of the presynaptic proteins, confirming in vitro findings. Measurement of extracellular DOPAC, a dopamine metabolite, following l -DOPA injection supported a role for RAB3B in enhancing the dopamine storage capacity of synaptic terminals. RAB3B overexpression in BE (2)-M17 cells was protective against toxins that simulate aspects of PD in vitro, including an oxidative stressor 6-hydroxydopamine (6-OHDA) and a proteasome inhibitor MG-132. Furthermore, RAB3B overexpression in rat SN both protected A9 DA neurons and resulted in behavioral improvement in a 6-OHDA retrograde lesion model of PD. These results suggest that RAB3B improves dopamine handling and storage capacity at presynaptic terminals, and confers protection to vulnerable DA neurons.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0912193106
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2009
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    Temporal, spatial and molecular pattern of dopaminergic neurodegeneration in the AAV-A53T α-synuclein rat model of Parkinson’s disease
    Elsevier BV ; 2022
    In:  Behavioural Brain Research Vol. 432 ( 2022-08), p. 113968-
    Details
    In: Behavioural Brain Research, Elsevier BV, Vol. 432 ( 2022-08), p. 113968-
    Type of Medium: Online Resource
    ISSN: 0166-4328
    URL: Article
    DOI: 10.1016/j.bbr.2022.113968
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 2013604-3
    SSG: 12
    SSG: 5,2
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  • 7
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    Characterization of 3,4-Methylenedioxymethamphetamine (MDMA) Enantiomers In Vitro and in the MPTP-Lesioned Primate: R -MDMA Reduces Severity of Dyskinesia, Whereas S -MDMA Extends Duration of ON-Time
    Society for Neuroscience ; 2011
    In:  The Journal of Neuroscience Vol. 31, No. 19 ( 2011-05-11), p. 7190-7198
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 31, No. 19 ( 2011-05-11), p. 7190-7198
    Abstract: l -3,4-Dihydroxyphenylalanine ( l -DOPA) is the most effective treatment for Parkinson's disease, but long-term l -DOPA administration is marred by the emergence of motor complications, namely, dyskinesia and a shortening of antiparkinsonian benefit (wearing-OFF). 3,4-Methylenedioxymethamphetamine (MDMA) is unique in that it exerts antidyskinetic effects and may enhance antiparkinsonian actions of l -DOPA. MDMA is composed of two enantiomers with different pharmacological profiles; here, we describe a novel enantiospecific synthesis of the two enantiomers and expand on the previous characterization of their pharmacology. R -MDMA (rectus-MDMA) is relatively selective for 5-HT 2A receptors, whereas S -MDMA (sinister-MDMA) inhibits both serotonin (SERT) and dopamine transporters (DAT; SERT/DAT ratio of 10 to 1). R - or S -MDMA (1, 3, and 10 mg/kg, s.c.) was administered in combination with l -DOPA (15 mg/kg, s.c.) to six female common marmosets ( Callithrix jacchus ) rendered parkinsonian by MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) administration. Motor disability, including parkinsonism and dyskinesia, and duration of antiparkinsonian benefit (ON-time) were evaluated. After the administration of R -MDMA (3 and 10 mg/kg), the severity of peak-dose dyskinesia was decreased (by 33 and 46%, respectively; p 〈 0.05); although total ON-time was unchanged (∼220 min), the duration of ON-time with disabling dyskinesia was decreased by 90 min when compared to l -DOPA alone (69% reduction; p 〈 0.05). S -MDMA (1 mg/kg) increased the total ON-time by 88 min compared to l -DOPA alone (34% increase; p 〈 0.05), though dyskinesia were exacerbated. These data suggest that racemic MDMA exerts simultaneous effects, reducing dyskinesia and extending ON-time, by 5-HT 2A antagonism and SERT-selective mixed monoamine uptake inhibition, which arise from its R and S enantiomers, respectively.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.1171-11.2011
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2011
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    Animal models of α-synucleinopathy for Parkinson disease drug development
    Springer Science and Business Media LLC ; 2017
    In:  Nature Reviews Neuroscience Vol. 18, No. 9 ( 2017-09), p. 515-529
    Details
    In: Nature Reviews Neuroscience, Springer Science and Business Media LLC, Vol. 18, No. 9 ( 2017-09), p. 515-529
    Type of Medium: Online Resource
    ISSN: 1471-003X , 1471-0048
    URL: Article
    DOI: 10.1038/nrn.2017.75
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
    detail.hit.zdb_id: 2028902-9
    SSG: 12
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  • 9
    Online Resource
    Online Resource
    An Endogenous Serine/Threonine Protein Phosphatase Inhibitor, G-Substrate, Reduces Vulnerability in Models of Parkinson's Disease
    Society for Neuroscience ; 2007
    In:  The Journal of Neuroscience Vol. 27, No. 31 ( 2007-08-01), p. 8314-8323
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 27, No. 31 ( 2007-08-01), p. 8314-8323
    Abstract: Relative neuronal vulnerability is a universal yet poorly understood feature of neurodegenerative diseases. In Parkinson's disease, dopaminergic (DA) neurons in the substantia nigra (SN) (A9) are particularly vulnerable, whereas adjacent DA neurons within the ventral tegmental area (A10) are essentially spared. Our previous laser capture microdissection and microarray study (Chung et al., 2005) demonstrated that molecular differences between these DA neurons may underlie their differential vulnerability. Here we show that G-substrate, an endogenous inhibitor of Ser/Thr protein phosphatases, exhibits higher expression in A10 compared with A9 DA neurons in both rodent and human midbrain. Overexpression of G-substrate protected dopaminergic BE(2)-M17 cells against toxins, including 6-OHDA and MG-132 (carbobenzoxy- l -leucyl- l -leucyl- l -leucinal), whereas RNA interference (RNAi)-mediated knockdown of endogenous G-substrate increased their vulnerability to these toxins. G-substrate reduced 6-OHDA-mediated protein phosphatase 2A (PP2A) activation in vitro and increased phosphorylated levels of PP2A targets including Akt, glycogen synthase kinase 3β, and extracellular signal-regulated kinase 2 but not p38. RNAi to Akt diminished the protective effect of G-substrate against 6-OHDA. In vivo , lentiviral delivery of G-substrate to the rat SN increased baseline levels of phosphorylated Akt and protected A9 DA neurons from 6-OHDA-induced toxicity. These results suggest that inherent differences in the levels of G-substrate contribute to the differential vulnerability of DA neurons and that enhancing G-substrate levels may be a neuroprotective strategy for the vulnerable A9 (SN) DA neurons in Parkinson's disease.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.1972-07.2007
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2007
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 10
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    Dynamic Changes in Presynaptic and Axonal Transport Proteins Combined with Striatal Neuroinflammation Precede Dopaminergic Neuronal Loss in a Rat Model of AAV α-Synucleinopathy
    Society for Neuroscience ; 2009
    In:  The Journal of Neuroscience Vol. 29, No. 11 ( 2009-03-18), p. 3365-3373
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 29, No. 11 ( 2009-03-18), p. 3365-3373
    Abstract: Little is known about key pathological events preceding overt neuronal degeneration in Parkinson's disease (PD) and α-synucleinopathy. Recombinant adeno-associated virus 2-mediated delivery of mutant (A53T) human α-synuclein into the substantia nigra (SN) under a neuron-specific synapsin promoter resulted in protracted neurodegeneration with significant dopaminergic (DA) neuron loss by 17 weeks. As early as 4 weeks, there was an increase in a dopamine metabolite, DOPAC and histologically, DA axons in the striatum were dystrophic with degenerative bulbs. Before neuronal loss, significant changes were identified in levels of proteins relevant to synaptic transmission and axonal transport in the striatum and the SN. For example, striatal levels of rabphilin 3A and syntaxin were reduced. Levels of anterograde transport motor proteins (KIF1A, KIF1B, KIF2A, and KIF3A) were decreased in the striatum, whereas retrograde motor proteins (dynein, dynamitin, and dynactin1) were increased. In contrast to reduced levels in the striatum, KIF1A and KIF2A levels were elevated in the SN. There were dramatic changes in cytoskeletal protein levels, with actin levels increased and α-/γ-tubulin levels reduced. In addition to these alterations, a neuroinflammatory response was observed at 8 weeks in the striatum, but not in the SN, demonstrated by increased levels of Iba-1, activated microglia and increased levels of proinflammatory cytokines, including IL-1β, IFN-γ and TNF-α. These results demonstrate that changes in proteins relevant to synaptic transmission and axonal transport coupled with neuroinflammation, precede α-synuclein-mediated neuronal death. These findings can provide ideas for antecedent biomarkers and presymptomatic interventions in PD.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.5427-08.2009
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2009
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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