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1.
J Parkinsons Dis ; 12(6): 1881-1896, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35466951

RESUMO

BACKGROUND: First-in-human studies to test the efficacy and safety of human embryonic stem cells (hESC)-derived dopaminergic cells in the treatment of Parkinson's disease (PD) are imminent. Pre-clinical studies using hESC-derived dopamine neuron transplants in rat models have indicated that the benefits parallel those shown with fetal tissue but have thus far failed to consider how ongoing L-DOPA administration might impact on the graft. OBJECTIVE: To determine whether L-DOPA impacts on survival and functional recovery following grafting of hESC-derived dopaminergic neurons. METHODS: Unilateral 6-OHDA lesioned rats were administered with either saline or L-DOPA prior to, and for 18 weeks following surgical implantation of dopaminergic neural progenitors derived from RC17 hESCs according to two distinct protocols in independent laboratories. RESULTS: Grafts from both protocols elicited reduction in amphetamine-induced rotations. Reduced L-DOPA-induced dyskinesia preceded the improvement in amphetamine-induced rotations. Furthermore, L-DOPA had no effect on overall survival (HuNu) or dopaminergic neuron content of the graft (TH positive cells) but did lead to an increase in the number of GIRK2 positive neurons. CONCLUSION: Critically, we found that L-DOPA was not detrimental to graft function, potentially enhancing graft maturation and promoting an A9 phenotype. Early improvement of L-DOPA-induced dyskinesia suggests that grafts may support the handling of exogenously supplied dopamine earlier than improvements in amphetamine-induced behaviours indicate. Given that one of the protocols will be employed in the production of cells for the European STEM-PD clinical trial, this is vital information for the management of patients and achieving optimal outcomes following transplantation of hESC-derived grafts for PD.


Assuntos
Discinesia Induzida por Medicamentos , Células-Tronco Embrionárias Humanas , Doença de Parkinson , Anfetaminas/uso terapêutico , Animais , Antiparkinsonianos/uso terapêutico , Modelos Animais de Doenças , Dopamina , Discinesia Induzida por Medicamentos/tratamento farmacológico , Humanos , Levodopa/uso terapêutico , Oxidopamina/uso terapêutico , Oxidopamina/toxicidade , Doença de Parkinson/tratamento farmacológico , Ratos , Ratos Sprague-Dawley
2.
Genes Brain Behav ; 21(4): e12799, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35118804

RESUMO

Mutations affecting DLG2 are emerging as a genetic risk factor associated with neurodevelopmental psychiatric disorders including schizophrenia, autism spectrum disorder, and bipolar disorder. Discs large homolog 2 (DLG2) is a member of the membrane-associated guanylate kinase protein superfamily of scaffold proteins, a component of the post-synaptic density in excitatory neurons and regulator of synaptic function and plasticity. It remains an important question whether and how haploinsuffiency of DLG2 contributes to impairments in basic behavioural and cognitive functions that may underlie symptomatic domains in patients that cross diagnostic boundaries. Using a heterozygous Dlg2 mouse model we examined the impact of reduced Dlg2 expression on functions commonly impaired in neurodevelopmental psychiatric disorders including motor co-ordination and learning, pre-pulse inhibition and habituation to novel stimuli. The heterozygous Dlg2 mice exhibited behavioural impairments in long-term motor learning and long-term habituation to a novel context, but not motor co-ordination, initial responses to a novel context, PPI of acoustic startle or anxiety. We additionally showed evidence for the reduced regulation of the synaptic plasticity-associated protein cFos in the motor cortex during motor learning. The sensitivity of selective behavioural and cognitive functions, particularly those dependent on synaptic plasticity, to reduced expression of DLG2 give further credence for DLG2 playing a critical role in specific brain functions but also a mechanistic understanding of symptom expression shared across psychiatric disorders.


Assuntos
Transtorno do Espectro Autista , Animais , Ansiedade/genética , Guanilato Quinases/genética , Guanilato Quinases/metabolismo , Heterozigoto , Humanos , Proteínas de Membrana , Camundongos , Plasticidade Neuronal , Proteínas Supressoras de Tumor
3.
Genes Brain Behav ; 21(4): e12797, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35075790

RESUMO

Genetic studies implicate disruption to the DLG2 gene in copy number variants as increasing risk for schizophrenia, autism spectrum disorders and intellectual disability. To investigate psychiatric endophenotypes associated with DLG2 haploinsufficiency (and concomitant PSD-93 protein reduction) a novel clinically relevant Dlg2+/- rat was assessed for abnormalities in anxiety, sensorimotor gating, hedonic reactions, social behaviour, and locomotor response to the N-Methyl-D-aspartic acid receptor antagonist phencyclidine. Dlg gene and protein expression were also investigated to assess model validity. Reductions in PSD-93 messenger RNA and protein were observed in the absence of compensation by other related genes or proteins. Behaviourally Dlg2+/- rats show a potentiated locomotor response to phencyclidine, as is typical of psychotic disorder models, in the absence of deficits in the other behavioural phenotypes assessed here. This shows that the behavioural effects of Dlg2 haploinsufficiency may specifically relate to psychosis vulnerability but are subtle, and partially dissimilar to behavioural deficits previously reported in Dlg2+/- mouse models demonstrating issues surrounding the comparison of models with different aetiology and species. Intact performance on many of the behavioural domains assessed here, such as anxiety and reward processing, will remove these as confounds when continuing investigation into this model using more complex cognitive tasks.


Assuntos
Guanilato Quinases , Haploinsuficiência , Esquizofrenia , Proteínas Supressoras de Tumor , Animais , Modelos Animais de Doenças , Guanilato Quinases/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana , Camundongos , Fenciclidina/farmacologia , Ratos , Esquizofrenia/genética , Esquizofrenia/metabolismo , Comportamento Social , Proteínas Supressoras de Tumor/genética
4.
Mol Cell Neurosci ; 68: 186-93, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26253862

RESUMO

The cellular prion protein has been identified as a metalloprotein that binds copper. There have been some suggestions that prion protein also influences zinc and manganese homeostasis. In this study we used a series of cell lines to study the levels of zinc and manganese under different conditions. We overexpressed either the prion protein or known transporters for zinc and manganese to determine relations between the prion protein and both manganese and zinc homeostasis. Our observations supported neither a link between the prion protein and zinc metabolism nor any effect of altered zinc levels on prion protein expression or cellular infection with prions. In contrast we found that a gain of function mutant of a manganese transporter caused reduction of manganese levels in prion infected cells, loss of observable PrP(Sc) in cells and resistance to prion infection. These studies strengthen the link between manganese and prion disease.


Assuntos
ATPases Transportadoras de Cálcio/genética , Proteínas de Membrana Transportadoras/genética , Mutação/genética , Príons/metabolismo , Animais , ATPases Transportadoras de Cálcio/metabolismo , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Linhagem Celular , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Endopeptidase K/farmacologia , Manganês/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Receptores de AMPA/genética , Receptores de AMPA/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transfecção , Zinco/metabolismo , Fator MTF-1 de Transcrição
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