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1.
J Neurosci ; 44(26)2024 06 26.
Artículo en Inglés | MEDLINE | ID: mdl-38664012

RESUMEN

l-DOPA-induced dyskinesia (LID) is a debilitating motor side effect arising from chronic dopamine (DA) replacement therapy with l-DOPA for the treatment of Parkinson's disease. LID is associated with supersensitivity of striatal dopaminergic signaling and fluctuations in synaptic DA following each l-DOPA dose, shrinking the therapeutic window. The heterogeneous composition of the striatum, including subpopulations of medium spiny output neurons (MSNs), interneurons, and supporting cells, complicates the identification of cell(s) underlying LID. We used single-nucleus RNA sequencing (snRNA-seq) to establish a comprehensive striatal transcriptional profile during LID development. Male hemiparkinsonian mice were treated with vehicle or l-DOPA for 1, 5, or 10 d, and striatal nuclei were processed for snRNA-seq. Analyses indicated a limited population of DA D1 receptor-expressing MSNs (D1-MSNs) formed three subclusters in response to l-DOPA treatment and expressed cellular markers of activation. These activated D1-MSNs display similar transcriptional changes previously associated with LID; however, their prevalence and transcriptional behavior were differentially influenced by l-DOPA experience. Differentially expressed genes indicated acute upregulation of plasticity-related transcription factors and mitogen-activated protein kinase signaling, while repeated l-DOPA-induced synaptic remodeling, learning and memory, and transforming growth factor-ß (TGF-ß) signaling genes. Notably, repeated l-DOPA sensitized Inhba, an activin subunit of the TGF-ß superfamily, in activated D1-MSNs, and its pharmacological inhibition impaired LID development, suggesting that activin signaling may play an essential role in LID. These data suggest distinct subsets of D1-MSNs become differentially l-DOPA-responsive due to aberrant induction of molecular mechanisms necessary for neuronal entrainment, similar to processes underlying hippocampal learning and memory.


Asunto(s)
Cuerpo Estriado , Discinesia Inducida por Medicamentos , Levodopa , Ratones Endogámicos C57BL , Animales , Levodopa/efectos adversos , Levodopa/toxicidad , Discinesia Inducida por Medicamentos/metabolismo , Masculino , Ratones , Cuerpo Estriado/metabolismo , Cuerpo Estriado/efectos de los fármacos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D1/genética , Antiparkinsonianos/efectos adversos , Antiparkinsonianos/farmacología , Neuronas/efectos de los fármacos , Neuronas/metabolismo
2.
Neurobiol Dis ; 201: 106685, 2024 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-39343248

RESUMEN

Altered interaction between striatonigral dopaminergic (DA) inputs and local acetylcholine (ACh) in striatum has long been hypothesized to play a central role in the pathophysiology of dystonia and dyskinesia. Indeed, previous research using several genetic mouse models of human isolated dystonia identified a shared endophenotype with paradoxical excitation of striatal cholinergic interneuron (ChIs) activity in response to activation of dopamine D2 receptors (D2R). These mouse models lack a dystonic motor phenotype, which leaves a critical gap in comprehending the role of DA and ACh transmission in the manifestations of dystonia. To tackle this question, we used a combination of ex vivo slice physiology and in vivo monitoring of striatal ACh dynamics in the inducible, phenotypically penetrant, transgenic mouse model of paroxysmal non-kinesiogenic dyskinesia (PNKD), an animal with both dystonic and dyskinetic features. We found that, similarly to genetic models of isolated dystonia, the PNKD mouse displays D2R-induced paradoxical excitation of ChI firing in ex vivo striatal brain slices. In vivo, caffeine triggers dystonic symptoms while reversing the D2R-mediated excitation of ChIs and desynchronizing ACh release in PNKD mice. In WT littermate controls, caffeine stimulates spontaneous locomotion through a similar but reversed mechanism involving an excitatory switch of the D2R control of ChI activity, associated with enhanced synchronization of ACh release. These observations suggest that the "paradoxical excitation" of cholinergic interneurons described in isolated dystonia models could represent a compensatory or protective mechanism that prevents manifestation of movement abnormalities and that phenotypic dystonia is possible only when this is absent. These findings also suggest that D2Rs may play an important role in synchronizing the ChI network leading to rhythmic ACh release during heightened movement states. Dysfunction of this interaction and corresponding desynchrony of ACh release may contribute to aberrant movements.


Asunto(s)
Acetilcolina , Cuerpo Estriado , Modelos Animales de Enfermedad , Ratones Transgénicos , Receptores de Dopamina D2 , Animales , Cuerpo Estriado/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D2/genética , Acetilcolina/metabolismo , Neuronas Colinérgicas/metabolismo , Ratones , Interneuronas/metabolismo , Interneuronas/fisiología , Transmisión Sináptica/fisiología , Cafeína/farmacología , Distonía/genética , Distonía/fisiopatología , Distonía/metabolismo , Masculino , Ratones Endogámicos C57BL
3.
Curr Opin Neurol ; 37(4): 409-413, 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-38780079

RESUMEN

PURPOSE OF REVIEW: to review recent progress in the development and use of continuous levodopa therapies in Parkinson disease (PD). RECENT FINDINGS: Levodopa/Carbidopa intestinal gel (LCIG) is a continuous levodopa therapy which is widely used in the United States, Europe and other countries and is effective at reducing 'off' time. Recent work has shown that LCIG can be useful in managing dyskinesias and can improve nonmotor symptoms and quality of life. Several studies have shown good long-term effectiveness of LCIG. Recent data support the cost-effectiveness of this treatment strategy. Subcutaneous (SC) delivery of levodopa is a newer strategy that avoids the need for a surgically placed gastric tube. Two different products enabling SC delivery of levodopa are in development: ND0612 and foslevodopa/foscarbidopa. Both have recently been shown to reduce 'off' time in randomized, double-blind trials. Adverse effects of SC levodopa are primarily related to skin reactions at the infusion site. SUMMARY: Continuous levodopa therapies can be used to treat Parkinson disease motor fluctuations that cannot be managed with standard oral therapies. They may also improve nonmotor symptoms, and improve overall quality of life in patients with advanced PD.


Asunto(s)
Antiparkinsonianos , Carbidopa , Levodopa , Enfermedad de Parkinson , Humanos , Levodopa/administración & dosificación , Levodopa/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/uso terapéutico , Carbidopa/administración & dosificación , Carbidopa/uso terapéutico , Combinación de Medicamentos , Infusiones Subcutáneas/métodos
4.
J Neuroinflammation ; 21(1): 216, 2024 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-39218899

RESUMEN

Parkinson's disease (PD) is characterized by neuroinflammation, progressive loss of dopaminergic neurons, and accumulation of α-synuclein (α-Syn) into insoluble aggregates called Lewy pathology. The Line 61 α-Syn mouse is an established preclinical model of PD; Thy-1 is used to promote human α-Syn expression, and features of sporadic PD develop at 9-18 months of age. To accelerate the PD phenotypes, we injected sonicated human α-Syn preformed fibrils (PFFs) into the striatum, which produced phospho-Syn (p-α-Syn) inclusions in the substantia nigra pars compacta and significantly increased MHC Class II-positive immune cells. Additionally, there was enhanced infiltration and activation of innate and adaptive immune cells in the midbrain. We then used this new model, Line 61-PFF, to investigate the effect of inhibiting the JAK/STAT signaling pathway, which is critical for regulation of innate and adaptive immune responses. After administration of the JAK1/2 inhibitor AZD1480, immunofluorescence staining showed a significant decrease in p-α-Syn inclusions and MHC Class II expression. Flow cytometry showed reduced infiltration of CD4+ T-cells, CD8+ T-cells, CD19+ B-cells, dendritic cells, macrophages, and endogenous microglia into the midbrain. Importantly, single-cell RNA-Sequencing analysis of CD45+ cells from the midbrain identified 9 microglia clusters, 5 monocyte/macrophage (MM) clusters, and 5 T-cell (T) clusters, in which potentially pathogenic MM4 and T3 clusters were associated with neuroinflammatory responses in Line 61-PFF mice. AZD1480 treatment reduced cell numbers and cluster-specific expression of the antigen-presentation genes H2-Eb1, H2-Aa, H2-Ab1, and Cd74 in the MM4 cluster and proinflammatory genes such as Tnf, Il1b, C1qa, and C1qc in the T3 cluster. Together, these results indicate that inhibiting the JAK/STAT pathway suppresses the activation and infiltration of innate and adaptive cells, reducing neuroinflammation in the Line 61-PFF mouse model.


Asunto(s)
Modelos Animales de Enfermedad , Enfermedades Neuroinflamatorias , Enfermedad de Parkinson , Factores de Transcripción STAT , Transducción de Señal , alfa-Sinucleína , Animales , Ratones , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Factores de Transcripción STAT/metabolismo , Factores de Transcripción STAT/antagonistas & inhibidores , Factores de Transcripción STAT/genética , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/inmunología , Humanos , Ratones Transgénicos , Ratones Endogámicos C57BL , Quinasas Janus/metabolismo , Quinasas Janus/antagonistas & inhibidores , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , Trastornos Parkinsonianos/inmunología , Pirimidinas/farmacología
5.
Mov Disord ; 39(6): 929-933, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38576081

RESUMEN

Basic Science is crucial for the advancement of clinical care for Movement Disorders. Here, we provide brief updates on how basic science is important for understanding disease mechanisms, disease prevention, disease diagnosis, development of novel therapies and to establish the basis for personalized medicine. We conclude the viewpoint by a call to action to further improve interactions between clinician and basic scientists. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Asunto(s)
Trastornos del Movimiento , Humanos , Trastornos del Movimiento/terapia , Investigación Biomédica Traslacional/métodos , Medicina de Precisión/métodos
6.
Mov Disord ; 39(4): 706-714, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38318953

RESUMEN

BACKGROUND: Early identification of subjective cognitive complaints (SCC) in Parkinson's disease (PD) may improve patient care if it predicts cognition-related functional impairment (CFI). OBJECTIVES: The aim was to determine the cross-sectional and longitudinal association between SCC and CFI in PD. METHODS: Data were obtained from Fox Insight, an online longitudinal study that collects PD patient-reported outcomes. Participants completed a PD Patient Report of Problems that asked participants for their five most bothersome disease problems. SCCs were placed into eight categories through human-in-the-loop curation and classification. CFI had a Penn Parkinson's Daily Activities Questionnaire (PDAQ-15) score ≤49. Cox proportional hazards models and Kaplan-Meier survival analyses determined if baseline SCC was associated with incident CFI. RESULTS: The PD-PROP cohort (N = 21,160) was 55.8% male, mean age was 65.9 years, and PD duration was 4.8 years. At baseline, 31.9% (N = 6750) of participants reported one or more SCCs among their five most bothersome problems, including memory (13.2%), language/word finding (12.5%), and concentration/attention (9.6%). CFI occurred in 34.7% (N = 7332) of participants. At baseline, SCC was associated with CFI (P-value <0.001). SCC at baseline was associated with incident CFI (hazard ratio [HR] = 1.58 [95% confidence interval: 1.45, 1.72], P-value <0.001), as did cognitive impairment not otherwise specified (HR = 2.31), executive abilities (HR = 1.97), memory (HR = 1.85), and cognitive slowing (HR = 1.77) (P-values <0.001). Kaplan-Meier curves showed that by year 3 an estimated 45% of participants with any SCC at baseline developed new-onset CFI. CONCLUSIONS: Self-reported bothersome cognitive complaints are associated with new-onset CFI in PD. Remote electronic assessment can facilitate widespread use of patient self-report at population scale. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Asunto(s)
Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/psicología , Masculino , Femenino , Anciano , Persona de Mediana Edad , Estudios Longitudinales , Estudios Transversales , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/etiología , Disfunción Cognitiva/fisiopatología , Actividades Cotidianas , Pruebas Neuropsicológicas , Cognición/fisiología
7.
J Immunol ; 208(8): 2054-2066, 2022 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-35379749

RESUMEN

Neurobehavioral disorders and brain abnormalities have been extensively reported in both Crohn's disease and ulcerative colitis patients. However, the mechanism causing neuropathological disorders in inflammatory bowel disease patients remains unknown. Studies have linked the Th17 subset of CD4+ T cells to brain diseases associated with neuroinflammation and cognitive impairment, including multiple sclerosis, ischemic brain injury, and Alzheimer's disease. To better understand how CD4+ T lymphocytes contribute to brain pathology in chronic intestinal inflammation, we investigated the development of brain inflammation in the T cell transfer model of chronic colitis. Our findings demonstrate that CD4+ T cells infiltrate the brain of colitic Rag1 -/- mice in proportional levels to colitis severity. Colitic mice developed hypothalamic astrogliosis that correlated with neurobehavioral disorders. Moreover, the brain-infiltrating CD4+ T cells expressed Th17 cell transcription factor retinoic acid-related orphan receptor γt (RORγt) and displayed a pathogenic Th17 cellular phenotype similar to colonic Th17 cells. Adoptive transfer of RORγt-deficient naive CD4+ T cells failed to cause brain inflammation and neurobehavioral disorders in Rag1 -/- recipients, with significantly less brain infiltration of CD4+ T cells. The finding is mirrored in chronic dextran sulfate sodium-induced colitis in Rorcfl/fl Cd4-Cre mice that showed lower frequency of brain-infiltrating CD4+ T cells and astrogliosis despite onset of significantly more severe colitis compared with wild-type mice. These findings suggest that pathogenic RORγt+CD4+ T cells that aggravate colitis migrate preferentially into the brain, contributing to brain inflammation and neurobehavioral disorders, thereby linking colitis severity to neuroinflammation.


Asunto(s)
Colitis , Encefalitis , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/inmunología , Animales , Linfocitos T CD4-Positivos/metabolismo , Proteínas Portadoras , Colitis/patología , Modelos Animales de Enfermedad , Gliosis/complicaciones , Gliosis/patología , Proteínas de Homeodominio/genética , Humanos , Inflamación/patología , Ratones , Ratones Endogámicos C57BL , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Receptores de Ácido Retinoico , Células Th17/metabolismo
8.
Mov Disord ; 38(5): 743-754, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36853618

RESUMEN

OBJECTIVE: To assess the presence of brain and systemic inflammation in subjects newly diagnosed with Parkinson's disease (PD). BACKGROUND: Evidence for a pathophysiologic role of inflammation in PD is growing. However, several key gaps remain as to the role of inflammation in PD, including the extent of immune activation at early stages, potential effects of PD treatments on inflammation and whether pro-inflammatory signals are associated with clinical features and/or predict more rapid progression. METHODS: We enrolled subjects with de novo PD (n = 58) and age-matched controls (n = 62). Subjects underwent clinical assessments, including the Movement Disorder Society-United Parkinson's Disease rating scale (MDS-UPDRS). Comprehensive cognitive assessment meeting MDS Level II criteria for mild cognitive impairment testing was performed. Blood was obtained for flow cytometry and cytokine/chemokine analyses. Subjects underwent imaging with 18 F-DPA-714, a translocator protein 18kd ligand, and lumbar puncture if eligible and consented. RESULTS: Baseline demographics and medical history were comparable between groups. PD subjects showed significant differences in University of Pennsylvania Smell Identification Test, Schwab and England Activities of Daily Living, Scales for Outcomes in PD autonomic dysfunction, and MDS-UPDRS scores. Cognitive testing demonstrated significant differences in cognitive composite, executive function, and visuospatial domain scores at baseline. Positron emission tomography imaging showed increased 18 F-DPA-714 signal in PD subjects. 18 F-DPA-714 signal correlated with several cognitive measures and some chemokines. CONCLUSIONS: 18 F-DPA-714 imaging demonstrated increased central inflammation in de novo PD subjects compared to controls. Longitudinal follow-up will be important to determine whether the presence of inflammation predicts cognitive decline. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Asunto(s)
Disfunción Cognitiva , Enfermedad de Parkinson , Humanos , Actividades Cotidianas , Encéfalo/metabolismo , Función Ejecutiva , Progresión de la Enfermedad
9.
Neurobiol Dis ; 166: 105650, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35139431

RESUMEN

This review provides an overview of the synaptic dysfunctions of neuronal circuits and underlying neurochemical alterations observed in the hyperkinetic movement disorders, dystonia and dyskinesia. These disorders exhibit similar changes in expression of synaptic plasticity and neuromodulation. This includes alterations in physical attributes of synapses, synaptic protein expression, and neurotransmitter systems, such as glutamate and gamma-aminobutyric acid (GABA), and neuromodulators, such as dopamine, acetylcholine, serotonin, adenosine, and endocannabinoids. A full understanding of the mechanisms and consequences of disruptions in synaptic function and plasticity will lend insight into the development of these disorders and new ways to combat maladaptive changes.


Asunto(s)
Discinesias , Distonía , Trastornos Distónicos , Antiparkinsonianos , Cuerpo Estriado/metabolismo , Discinesias/metabolismo , Distonía/inducido químicamente , Distonía/metabolismo , Trastornos Distónicos/inducido químicamente , Trastornos Distónicos/metabolismo , Humanos , Levodopa/efectos adversos
11.
Brain ; 144(7): 2047-2059, 2021 08 17.
Artículo en Inglés | MEDLINE | ID: mdl-33704423

RESUMEN

α-Synuclein, a key pathological component of Parkinson's disease, has been implicated in the activation of the innate and adaptive immune system. This immune activation includes microgliosis, increased inflammatory cytokines, and the infiltration of T cells into the CNS. More recently, peripherally circulating CD4 and CD8 T cells derived from individuals with Parkinson's disease have been shown to produce Th1/Th2 cytokines in response to α-synuclein, suggesting there may be a chronic memory T cell response present in Parkinson's disease. To understand the potential effects of these α-syn associated T cell responses we used an α-synuclein overexpression mouse model, T cell-deficient mice, and a combination of immunohistochemistry and flow cytometry. In this study, we found that α-synuclein overexpression in the midbrain of mice leads to the upregulation of the major histocompatibility complex II (MHCII) protein on CNS myeloid cells as well as the infiltration of IFNγ producing CD4 and CD8 T cells into the CNS. Interestingly, genetic deletion of TCRß or CD4, as well as the use of the immunosuppressive drug fingolimod, were able to reduce the CNS myeloid MHCII response to α-synuclein. Furthermore, we observed that CD4-deficient mice were protected from the dopaminergic cell loss observed due to α-syn overexpression. These results suggest that T cell responses associated with α-synuclein pathology may be damaging to key areas of the CNS in Parkinson's disease and that targeting these T cell responses could be an avenue for disease modifying treatments.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Encefalitis/inmunología , Encefalitis/patología , Degeneración Nerviosa/inmunología , Enfermedad de Parkinson/inmunología , Animales , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Degeneración Nerviosa/patología , Enfermedad de Parkinson/patología , alfa-Sinucleína/inmunología
12.
Mov Disord ; 36(1): 16-24, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32357266

RESUMEN

Parkinson's disease is a progressive and debilitating disorder that has so far eluded attempts to develop disease-modifying treatment. Both epidemiological and genetic studies support a role of neuroinflammation in the pathophysiology of Parkinson's disease. Postmortem studies and experimental analyses suggest the involvement of both innate and adaptive immunity in the degenerative process. There is also some circumstantial evidence for effects of immune therapies on the disease. In the present article, we review 10 unanswered questions related to neuroinflammatory processes in Parkinson's disease with the goal of stimulating research in the field and accelerating the clinical development of neuroprotective therapies based on anti-inflammatory strategies. © 2020 International Parkinson and Movement Disorder Society.


Asunto(s)
Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/complicaciones , alfa-Sinucleína
13.
J Immunol ; 203(1): 84-92, 2019 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-31085590

RESUMEN

Tau protein is found to be aggregated and hyperphosphorylated (p-tau) in many neurologic disorders, including Parkinson disease (PD) and related parkinsonisms, Alzheimer disease, traumatic brain injury, and even in normal aging. Although not known to produce autoimmune responses, we hypothesized that the appearance of aggregated tau and p-tau with disease could activate the immune system. We thus compared T cell responses to tau and p-tau-derived peptides between PD patients, age-matched healthy controls, and young healthy controls (<35 y old; who are less likely to have high levels of tau aggregates). All groups exhibited CD4+ T cell responses to tau-derived peptides, which were associated with secretion of IFN-γ, IL-5, and/or IL-4. The PD and control participants exhibited a similar magnitude and breadth of responses. Some tau-derived epitopes, consisting of both unmodified and p-tau residues, were more highly represented in PD participants. These results were verified in an independent set of PD and control donors (either age-matched or young controls). Thus, T cells recognizing tau epitopes escape central and peripheral tolerance in relatively high numbers, and the magnitude and nature of these responses are not modulated by age or PD disease.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Péptidos/inmunología , Proteínas tau/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Autoinmunidad , Células Cultivadas , Selección Clonal Mediada por Antígenos , Femenino , Humanos , Tolerancia Inmunológica , Masculino , Persona de Mediana Edad , Fosforilación , Agregación Patológica de Proteínas , Especificidad del Receptor de Antígeno de Linfocitos T , Adulto Joven
14.
J Neurosci ; 39(36): 7195-7205, 2019 09 04.
Artículo en Inglés | MEDLINE | ID: mdl-31320448

RESUMEN

Clinical and experimental data indicate striatal cholinergic dysfunction in dystonia, a movement disorder typically resulting in twisted postures via abnormal muscle contraction. Three forms of isolated human dystonia result from mutations in the TOR1A (DYT1), THAP1 (DYT6), and GNAL (DYT25) genes. Experimental models carrying these mutations facilitate identification of possible shared cellular mechanisms. Recently, we reported elevated extracellular striatal acetylcholine by in vivo microdialysis and paradoxical excitation of cholinergic interneurons (ChIs) by dopamine D2 receptor (D2R) agonism using ex vivo slice electrophysiology in Dyt1ΔGAG/+ mice. The paradoxical excitation was caused by overactive muscarinic receptors (mAChRs), leading to a switch in D2R coupling from canonical Gi/o to noncanonical ß-arrestin signaling. We sought to determine whether these mechanisms in Dyt1ΔGAG/+ mice are shared with Thap1C54Y/+ knock-in and Gnal+/- knock-out dystonia models and to determine the impact of sex. We found Thap1C54Y/+ mice of both sexes have elevated extracellular striatal acetylcholine and D2R-induced paradoxical ChI excitation, which was reversed by mAChR inhibition. Elevated extracellular acetylcholine was absent in male and female Gnal+/- mice, but the paradoxical D2R-mediated ChI excitation was retained and only reversed by inhibition of adenosine A2ARs. The Gi/o-preferring D2R agonist failed to increase ChI excitability, suggesting a possible switch in coupling of D2Rs to ß-arrestin, as seen previously in a DYT1 model. These data show that, whereas elevated extracellular acetylcholine levels are not always detected across these genetic models of human dystonia, the D2R-mediated paradoxical excitation of ChIs is shared and is caused by altered function of distinct G-protein-coupled receptors.SIGNIFICANCE STATEMENT Dystonia is a common and often disabling movement disorder. The usual medical treatment of dystonia is pharmacotherapy with nonselective antagonists of muscarinic acetylcholine receptors, which have many undesirable side effects. Development of new therapeutics is a top priority for dystonia research. The current findings, considered in context with our previous investigations, establish a role for cholinergic dysfunction across three mouse models of human genetic dystonia: DYT1, DYT6, and DYT25. The commonality of cholinergic dysfunction in these models arising from diverse molecular etiologies points the way to new approaches for cholinergic modulation that may be broadly applicable in dystonia.


Asunto(s)
Neuronas Colinérgicas/metabolismo , Cuerpo Estriado/metabolismo , Proteínas de Unión al ADN/genética , Distonía/genética , Glucosamina 6-Fosfato N-Acetiltransferasa/genética , Chaperonas Moleculares/genética , Acetilcolina/metabolismo , Animales , Neuronas Colinérgicas/fisiología , Cuerpo Estriado/fisiopatología , Distonía/metabolismo , Distonía/fisiopatología , Espacio Extracelular/metabolismo , Femenino , Interneuronas/metabolismo , Interneuronas/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores de Dopamina D2/metabolismo , Receptores Muscarínicos/metabolismo , Potenciales Sinápticos , beta-Arrestinas/metabolismo
15.
Neurobiol Dis ; 134: 104708, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31837424

RESUMEN

Parkinson's disease (PD) is defined by motor symptoms such as tremor at rest, bradykinesia, postural instability, and stiffness. In addition to the classical motor defects that define PD, up to 80% of patients experience cognitive changes and psychiatric disturbances, referred to as PD dementia (PDD). Pathologically, PD is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and intracellular inclusions, called Lewy bodies and Lewy neurites, composed mostly of α-synuclein. Much of PD research has focused on the role of α-synuclein aggregates in degeneration of SNpc dopamine neurons because of the impact of loss of striatal dopamine on the classical motor phenotypes. However, abundant Lewy pathology is also found in other brain regions including the cortex and limbic brain regions such as the amygdala, which may contribute to non-motor phenotypes. Little is known about the consequences of α-synuclein inclusions in these brain regions, or in neuronal subtypes other than dopamine neurons. This project expands knowledge on how α-synuclein inclusions disrupt behavior, specifically non-motor symptoms of synucleinopathies. We show that bilateral injections of fibrils into the striatum results in robust bilateral α-synuclein inclusion formation in the cortex and amygdala. Inclusions in the amygdala and prefrontal cortex primarily localize to excitatory neurons, but unbiased stereology shows no significant loss of neurons in the amygdala or cortex. Fibril injected mice show defects in a social dominance behavioral task and fear conditioning, tasks that are associated with prefrontal cortex and amygdala function. Together, these observations suggest that seeded α-synuclein inclusion formation impairs behaviors associated with cortical and amygdala function, without causing cell loss, in brain areas that may play important roles in the complex cognitive features of PDD.


Asunto(s)
Amígdala del Cerebelo/patología , Conducta Animal/fisiología , Corteza Cerebral/patología , Cuerpos de Inclusión/patología , alfa-Sinucleína/metabolismo , Amígdala del Cerebelo/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Corteza Cerebral/metabolismo , Condicionamiento Clásico , Cuerpo Estriado/efectos de los fármacos , Femenino , Cuerpos de Inclusión/metabolismo , Masculino , Ratones Endogámicos C57BL , Neuronas/metabolismo , Neuronas/patología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/psicología , Prueba de Desempeño de Rotación con Aceleración Constante , alfa-Sinucleína/administración & dosificación
16.
Acta Neuropathol ; 139(5): 855-874, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31993745

RESUMEN

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by abnormal accumulation of alpha-synuclein (α-syn) in oligodendrocytes accompanied by inflammation, demyelination, and subsequent synapse and neuronal loss. Little is known about the mechanisms of neurodegeneration in MSA. However, recent work has highlighted the important role of the immune system to the pathophysiology of other synuclein-related diseases such as Parkinson's disease. In this study, we investigated postmortem brain tissue from MSA patients and control subjects for evidence of immune activation in the brain. We found a significant increase of HLA-DR+ microglia in the putamen and substantia nigra of MSA patient tissue compared to controls, as well as significant increases in CD3+, CD4+, and CD8+ T cells in these same brain regions. To model MSA in vivo, we utilized a viral vector that selectively overexpresses α-syn in oligodendrocytes (Olig001-SYN) with > 95% tropism in the dorsal striatum of mice, resulting in demyelination and neuroinflammation similar to that observed in human MSA. Oligodendrocyte transduction with this vector resulted in a robust inflammatory response, which included increased MHCII expression on central nervous system (CNS) resident microglia, and infiltration of pro-inflammatory monocytes into the CNS. We also observed robust infiltration of CD4 T cells into the CNS and antigen-experienced CD4 T cells in the draining cervical lymph nodes. Importantly, genetic deletion of TCR-ß or CD4 T cells attenuated α-syn-induced inflammation and demyelination in vivo. These results suggest that T cell priming and infiltration into the CNS are key mechanisms of disease pathogenesis in MSA, and therapeutics targeting T cells may be disease modifying.


Asunto(s)
Encéfalo/patología , Microglía/patología , Atrofia de Múltiples Sistemas/patología , Linfocitos T/patología , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones Endogámicos C57BL , Microglía/inmunología , Atrofia de Múltiples Sistemas/inmunología , Neuronas/patología , Oligodendroglía/patología , Enfermedad de Parkinson/patología
17.
Mov Disord ; 35(6): 1055-1061, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32251552

RESUMEN

BACKGROUND: Extensive scientific and clinical evidence indicates that continuous delivery of a dopaminergic agent is associated with significant reduction in motor complications compared with intermittent oral dosing with the same agent. There has been an intensive effort to develop a method of providing continuous plasma levels of a dopaminergic agent that avoids the need for surgical therapy or an infusion system. Studies in MPTP-treated monkeys demonstrate that once-weekly injections of polymer-linked rotigotine provide continuous plasma levels and antiparkinsonian benefits. METHODS: We performed a multicenter open-label, multiple-ascending-dose-ranging cohort study to evaluate the safety, tolerability, and pharmacokinetics of polymer-linked rotigotine in PD patients. RESULTS: A total of 19 patients were evaluated in 4 cohorts in doses of 20 50, 100, and 200 mg of polymer-linked rotigotine, administered subcutaneously once weekly. The study demonstrated remarkably stable dose-related plasma levels of total and free rotigotine with no accumulation or dumping. Treatment was generally safe and well tolerated. One subject in the 50-mg group discontinued because of hives, which cleared rapidly with antihistamine treatment. CONCLUSIONS: This study demonstrates that once-a-week subcutaneous administration of polymer-linked rotigotine provides relatively constant plasma levels of rotigotine and is safe and well tolerated. These findings suggest that this convenient method of delivery of rotigotine has the potential to treat or prevent motor complications in PD patients without the need for a surgical procedure or an infusion system. This approach may also prove applicable to other agents such as apomorphine that can be linked to this polymer © 2020 International Parkinson and Movement Disorder Society.


Asunto(s)
Enfermedad de Parkinson , Administración Cutánea , Estudios de Cohortes , Agonistas de Dopamina/uso terapéutico , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Plasma , Polímeros/uso terapéutico , Tetrahidronaftalenos/uso terapéutico , Tiofenos
18.
Mov Disord ; 35(7): 1253-1257, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32220093

RESUMEN

INTRODUCTION: Statins were proposed to be neuroprotective; however, the effects are unknown in progressive supranuclear palsy (PSP), a pure tauopathy. METHODS: Data of 284 PSP cases and 284 age-matched, sex-matched, and race-matched controls were obtained from the environmental and genetic PSP (ENGENE-PSP) study. Cases were evaluated with the PSP Rating Scale, Unified Parkinson's Disease Rating Scale, Mattis Dementia Rating Scale, and Neuropsychiatric Inventory. Statin associations with PSP risk, onset age, and disease features were analyzed. RESULTS: Univariate models showed lower PSP risk for type 1 statin users (simvastatin, lovastatin, pravastatin). After adjusting for confounding variables, statin use and lower PSP risk association remained only at a trend level. For PSP cases, type 1 statins were associated with 1-year older onset age; type 2 statins (atorvastatin, rosuvastatin) were associated with the lower PSP Rating Scale and Unified Parkinson's Disease Rating Scale. CONCLUSION: Statins may have inverse associations with PSP risk and motor impairment. Randomized prospective studies are required to confirm this effect. © 2020 International Parkinson and Movement Disorder Society.


Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas , Parálisis Supranuclear Progresiva , Tauopatías , Estudios de Casos y Controles , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Estudios Prospectivos , Parálisis Supranuclear Progresiva/tratamiento farmacológico , Parálisis Supranuclear Progresiva/epidemiología
20.
Neurobiol Dis ; 132: 104579, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31445160

RESUMEN

Dystonia and levodopa-induced dyskinesia (LID) are both hyperkinetic movement disorders. Dystonia arises most often spontaneously, although it may be seen after stroke, injury, or as a result of genetic causes. LID is associated with Parkinson's disease (PD), emerging as a consequence of chronic therapy with levodopa, and may be either dystonic or choreiform. LID and dystonia share important phenomenological properties and mechanisms. Both LID and dystonia are generated by an integrated circuit involving the cortex, basal ganglia, thalamus and cerebellum. They also share dysregulation of striatal cholinergic signaling and abnormalities of striatal synaptic plasticity. The long duration nature of both LID and dystonia suggests that there may be underlying epigenetic dysregulation as a proximate cause. While both may improve after interventions such as deep brain stimulation (DBS), neither currently has a satisfactory medical therapy, and many people are disabled by the symptoms of dystonia and LID. Further study of the fundamental mechanisms connecting these two disorders may lead to novel approaches to treatment or prevention.


Asunto(s)
Encéfalo/fisiopatología , Discinesia Inducida por Medicamentos/fisiopatología , Trastornos Distónicos/fisiopatología , Animales , Antiparkinsonianos/efectos adversos , Humanos , Levodopa/efectos adversos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología
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