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Träfflista för sökning "WFRF:(Cenci Angela M.) "

Sökning: WFRF:(Cenci Angela M.)

  • Resultat 41-47 av 47
  • Föregående 1234[5]
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  • Outeiro, Tiago F., et al. (författare)
  • From iPS Cells to Rodents and Nonhuman Primates : Filling Gaps in Modeling Parkinson's Disease
  • 2021
  • Ingår i: Movement Disorders. - : John Wiley & Sons Inc.. - 0885-3185. ; 36:4, s. 832-841
  • Tidskriftsartikel (refereegranskat)abstract
    • Parkinson's disease (PD) is primarily known as a movement disorder because of typical clinical manifestations associated with the loss of dopaminergic neurons in the substantia nigra. However, it is now widely recognized that PD is a much more complex condition, with multiple and severe nonmotor features implicating additional brain areas and organs in the disease process. Pathologically, typical forms of PD are characterized by the accumulation of α-synuclein-rich protein inclusions known as Lewy bodies and Lewy neurites, although other types of protein inclusions are also often present in the brain. Familial forms of PD have provided a wealth of information about molecular pathways leading to neurodegeneration, but only to add to the complexity of the problem and uncover new knowledge gaps. Therefore, modeling PD in the laboratory has become increasingly challenging. Here, we discuss knowledge gaps and challenges in the use of laboratory models for the study of a disease that is clinically heterogeneous and multifactorial. We propose that the combined use of patient-derived cells and animal models, along with current technological tools, will not only expand our molecular and pathophysiological understanding of PD, but also assist in the identification of therapeutic strategies targeting relevant pathogenic pathways.
  • Petersson, Per, et al. (författare)
  • Significance and translational value of high-frequency cortico-basal ganglia oscillations in Parkinson's disease
  • 2019
  • Ingår i: Journal of Parkinson's Disease. - : IOS Press. - 1877-7171 .- 1877-718X. ; 9:1, s. 183-196
  • Tidskriftsartikel (refereegranskat)abstract
    • The mechanisms and significance of basal ganglia oscillations is a fundamental research question engaging both clinical and basic investigators. In Parkinson's disease (PD), neural activity in basal ganglia nuclei is characterized by oscillatory patterns that are believed to disrupt the dynamic processing of movement-related information and thus generate motor symptoms. Beta-band oscillations associated with hypokinetic states have been reviewed in several excellent previous articles. Here we focus on faster oscillatory phenomena that have been reported in association with a diverse range of motor states. We review the occurrence of different types of fast oscillations and the evidence supporting their pathophysiological role. We also provide a general discussion on the definition, possible mechanisms, and translational value of synchronized oscillations of different frequencies in cortico-basal ganglia structures. Revealing how oscillatory phenomena are caused and spread in cortico-basal ganglia-thalamocortical networks will offer a key to unlock the neural codes of both motor and non-motor symptoms in PD. In preclinical therapeutic research, recording of oscillatory neural activities holds the promise to unravel mechanisms of action of current and future treatments.
  • Picconi, B, et al. (författare)
  • Abnormal Ca2+-calmodulin-dependent protein kinase II function mediates synaptic and motor deficits in experimental parkinsonism
  • 2004
  • Ingår i: Journal of Neuroscience. - : Society for Neuroscience. - 1529-2401. ; 24:23, s. 5283-5291
  • Tidskriftsartikel (refereegranskat)abstract
    • The NMDA receptor complex represents a key molecular element in the pathogenesis of long-term synaptic changes and motor abnormalities in Parkinson's disease (PD). Here we show that NMDA receptor 1 (NR1) subunit and postsynaptic density (PSD)-95 protein levels are selectively reduced in the PSD of dopamine (DA)-denervated striata. These effects are accompanied by an increase in striatal levels of alphaCa(2+)-calmodulin-dependent protein kinase II (alphaCaMKII) autophosphorylation, along with a higher recruitment of activated alphaCaMKII to the regulatory NMDA receptor NR2A-NR2B subunits. Acute treatment of striatal slices with R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaz epine hydrochloride, but not with L-sulpiride, mimicked the effect of DA denervation on both alphaCaMKII autophosphorylation and corticostriatal synaptic plasticity. In addition to normalizing alphaCaMKII autophosphorylation levels as well as assembly and anchoring of the kinase to the NMDA receptor complex, intrastriatal administration of the CaMKII inhibitors KN-93 (N-[2-[[[3-(4-chlorophenyl)-2-propenyl] methylamino] methyl] phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide) and antennapedia autocamtide-related inhibitory peptide II is able to reverse both the alterations in corticostriatal synaptic plasticity and the deficits in spontaneous motor behavior that are found in an animal model of PD. The same beneficial effects are produced by a regimen of L-3,4-dihydroxyphenylalanine(L-DOPA) treatment, which is able to normalize alphaCaMKII autophosphorylation. These data indicate that abnormal alphaCaMKII autophosphorylation plays a causal role in the alterations of striatal plasticity and motor behavior that follow DA denervation. Normalization of CaMKII activity may be an important underlying mechanism of the therapeutic action of L-DOPA in PD.
  • Refolo, Violetta, et al. (författare)
  • Progressive striatonigral degeneration in a transgenic mouse model of multiple system atrophy : translational implications for interventional therapies
  • 2018
  • Ingår i: Acta Neuropathologica Communications. - : BioMed Central (BMC). - 2051-5960. ; 6:1, s. 1-24
  • Tidskriftsartikel (refereegranskat)abstract
    • Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder characterized by widespread oligodendroglial cytoplasmic inclusions of filamentous α-synuclein, and neuronal loss in autonomic centres, basal ganglia and cerebellar circuits. It has been suggested that primary oligodendroglial α-synucleinopathy may represent a trigger in the pathogenesis of MSA, but the mechanisms underlying selective vulnerability and disease progression are unclear. The post-mortem analysis of MSA brains provides a static final picture of the disease neuropathology, but gives no clear indication on the sequence of pathogenic events in MSA. Therefore, alternative methods are needed to address these issues. We investigated selective vulnerability and disease progression in the transgenic PLP-α-syn mouse model of MSA characterized by targeted oligodendroglial α-synuclein overexpression aiming to provide a neuropathological correlate of motor deterioration. We show progressive motor deficits that emerge at 6 months of age and deteriorate up to 18 months of follow-up. The motor phenotype was associated with dopaminergic cell loss in the substantia nigra pars compacta at 6 months, followed by loss of striatal dopaminergic terminals and DARPP32-positive medium sized projection neurons at 12 months. Olivopontocerebellar motor loops remained spared in the PLP-α-syn model of MSA. These findings replicate progressive striatonigral degeneration underlying Parkinson-variant MSA. The initiation of the degenerative process was linked to an increase of soluble oligomeric α-synuclein species between 2 and 6 months. Early region-specific α-synuclein-associated activation profile of microglia was found in MSA substantia nigra. The role of abnormal neuroinflammatory signalling in disease progression was further supported by increased levels of CD68, CCL3, CCL5 and M-CSF with a peak in aged PLP-α-syn mice. In summary, transgenic PLP-α-syn mice show a distinctive oligodendroglial α-synucleinopathy that is associated with progressive striatonigral degeneration linked to abnormal neuroinflammatory response. The model provides a relevant tool for preclinical therapeutic target discovery for human Parkinson-variant MSA.
  • Schuster, Stefan, et al. (författare)
  • Antagonizing L-type Ca2+ Channel Reduces Development of Abnormal Involuntary Movement in the Rat Model of L-3,4-Dihydroxyphenylalanine-Induced Dyskinesia
  • 2009
  • Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223. ; 65:6, s. 518-526
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) leads to debilitating involuntary movements, termed L-DOPA-induced dyskinesia. Striatofugal medium spiny neurons (MSN) lose their dendritic spines and cortico-striatal glutamatergic synapses in PD and in experimental models of DA depletion. This loss of connectivity is triggered by a dysregulation of intraspine Cav1.3 L-type Ca2+ channels. Here we address the possible implication of DA denervation-induced spine pruning in the development of L-DOPA-induced dyskinesia. Methods: The L-type Ca2+ antagonist, isradipine was subcutaneously delivered to rats at the doses of .05, .1, or .2 mg/kg/day, for 4 weeks, starting the day after a unilateral nigrostriatal 6-hydroxydopamine (6-OHDA) lesion. Fourteen days later, L-DOPA treatment was initiated. Results: Isradipine-treated animals displayed a dose-dependent reduction in L-DOPA-induced rotational behavior and abnormal involuntary movements. Dendritic spine counting at electron microscopy level showed that isradipine (.2 mg/kg/day) prevented the 6-OHDA-induced spine loss and normalized preproenkephalin-A messenger RNA expression. Involuntary movements were not reduced when isradipine treatment was started concomitantly with L-DOPA. Conclusions: These results indicate that isradipine, at a therapeutically relevant dose, might represent a treatment option for preventing L-DOPA-induced dyskinesia in PD.
  • Sebastianutto, Irene, et al. (författare)
  • D1-mGlu5 heteromers mediate noncanonical dopamine signaling in Parkinson’s disease
  • 2020
  • Ingår i: Journal of Clinical Investigation. - : The American Society for Clinical Investigation. - 0021-9738. ; 130:3, s. 1168-1184
  • Tidskriftsartikel (refereegranskat)abstract
    • Dopamine receptor D1 modulates glutamatergic transmission in cortico-basal ganglia circuits and represents a major target of L-DOPA therapy in Parkinson’s disease. Here we show that D1 and metabotropic glutamate type 5 (mGlu5) receptors can form previously unknown heteromeric entities with distinctive functional properties. Interacting with Gq proteins, cell-surface D1-mGlu5 heteromers exacerbated PLC signaling and intracellular calcium release in response to either glutamate or dopamine. In rodent models of Parkinson’s disease, D1-mGlu5 nanocomplexes were strongly upregulated in the dopamine-denervated striatum, resulting in a synergistic activation of PLC signaling by D1 and mGlu5 receptor agonists. In turn, D1-mGlu5–dependent PLC signaling was causally linked with excessive activation of extracellular signal–regulated kinases in striatal neurons, leading to dyskinesia in animals treated with L-DOPA or D1 receptor agonists. The discovery of D1-mGlu5 functional heteromers mediating maladaptive molecular and motor responses in the dopamine-denervated striatum may prompt the development of new therapeutic principles for Parkinson’s disease.
  • Valastro, Barbara, et al. (författare)
  • Expression pattern of JunD after acute or chronic l-DOPA treatment: Comparison with DeltaFosB.
  • 2007
  • Ingår i: Neuroscience. - : Elsevier. - 1873-7544 .- 0306-4522. ; 144:Oct 19, s. 198-207
  • Tidskriftsartikel (refereegranskat)abstract
    • In this study, we have used 6-hydroxydopamine-lesioned rats to examine changes in striatal junD and fosB/Delta fosB expression induced by acute and chronic treatment with (L)-DOPA (5 and 15 days). Changes at the protein levels were studied using Western immunoblotting while mRNA changes were compared using in situ hybridization histochemistry. We observed a significant increase in the level of Delta FosB proteins after chronic treatment with L-DOPA, an effect that was not observed for JunD proteins. In addition, the upregulation of Delta FosB was already present after an acute treatment but increased upon chronic treatment. By contrast, junD and Delta fosB mRNA were both upregulated significantly above control levels after an acute injection of L-DOPA. In conclusion, this study suggests a differential expression pattern of junD and Delta fosB in a rat model of L-DOPA-induced dyskinesia. The upregulation of Delta FosB protein, but not JunD, is likely to reflect an increased stability of the Delta FosB proteins without ongoing enhanced transcription of the encoding genes. (c) 2006 IBRO. Published by Elsevier Ltd. All rights reserved.
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  • Resultat 41-47 av 47
  • Föregående 1234[5]

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