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Levodopa-induced dyskinesia (LID) is an intractable motor complication arising in Parkinson's disease with the progression of disease and chronic treatment of levodopa. However, the specific cell assemblies mediating dyskinesia have not been fully elucidated. Here, we utilize the activity-dependent tool to identify three brain regions (globus pallidus external segment [GPe], parafascicular thalamic nucleus, and subthalamic nucleus) that specifically contain dyskinesia-activated ensembles. An intensity-dependent hyperactivity in the dyskinesia-activated subpopulation in GPe (GPeTRAPed in LID) is observed during dyskinesia. Optogenetic inhibition of GPeTRAPed in LID significantly ameliorates LID, whereas reactivation of GPeTRAPed in LID evokes dyskinetic behavior in the levodopa-off state. Simultaneous chemogenetic reactivation of GPeTRAPed in LID and another previously reported ensemble in striatum fully reproduces the dyskinesia induced by high-dose levodopa. Finally, we characterize GPeTRAPed in LID as a subset of prototypic neurons in GPe. These findings provide theoretical foundations for precision medication and modulation of LID in the future.
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Discinesia Inducida por Medicamentos , Globo Pálido , Levodopa , Levodopa/efectos adversos , Globo Pálido/efectos de los fármacos , Globo Pálido/fisiopatología , Discinesia Inducida por Medicamentos/fisiopatología , Discinesia Inducida por Medicamentos/patología , Animales , Neuronas/efectos de los fármacos , Masculino , Optogenética , Ratones , Enfermedad de Parkinson/tratamiento farmacológico , Humanos , Núcleo Subtalámico/efectos de los fármacos , Núcleo Subtalámico/fisiopatologíaRESUMEN
So far, over 20 causative genes of monogenic Parkinson's disease (PD) have been identified. Some causative genes of non-parkinsonian entities may also manifest with parkinsonism mimicking PD. This study aimed to investigate the genetic characteristics of clinically diagnosed PD with early onset age or family history. A total of 832 patients initially diagnosed with PD were enrolled, of which, 636 were classified into the early-onset group and 196 were classified into the familial late-onset group. The genetic testing included the multiplex ligation-dependent probe amplification and next generation sequencing (target sequencing or whole-exome sequencing). The dynamic variants of spinocerebellar ataxia were tested in probands with family history. In the early-onset group, 30.03% of patients (191/636) harbored pathogenic/likely pathogenic (P/LP) variants in known PD-related genes (CHCHD2, DJ-1, GBA (heterozygous), LRRK2, PINK1, PRKN, PLA2G6, SNCA and VPS35). Variants in PRKN were the most prevalent, accounting for 15.72% of the early-onset patients, followed by GBA (10.22%), and PLA2G6 (1.89%). And 2.52% (16/636) had P/LP variants in causative genes of other diseases (ATXN3, ATXN2, GCH1, TH, MAPT, GBA (homozygous)). In the familial late-onset group, 8.67% of patients (17/196) carried P/LP variants in known PD-related genes (GBA (heterozygous), HTRA2, SNCA) and 2.04% (4/196) had P/LP variants in other genes (ATXN2, PSEN1, DCTN1). Heterozygous GBA variants (7.14%) were the most common genetic cause found in familial late-onset patients. Genetic testing is of vital importance in differential diagnosis especially in early-onset and familial PD. Our findings may also provide some clues to the nomenclature of genetic movement disorders.
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INTRODUCTION: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of autosomal dominantly inherited Parkinson's disease (PD). Recently, a novel pathogenic variant (N1437D; c.4309A > G; NM_98578) in the LRRK2 gene has been identified in three Chinese families with PD. In this study, we describe a Chinese family with autosomal dominant PD that segregated with the N1437D mutation. A detailed clinical and neuroimaging characterization of the affected family members is reported. We also sought to investigate the functional mechanisms by which the detected mutation could cause PD. METHODS: We characterized the clinical and imaging phenotype of a Chinese pedigree with autosomal dominant PD. We searched for a disease-causing mutation by targeted sequencing and multiple ligation-dependent probe amplification. The functional impact of the mutation was investigated in terms of LRRK2 kinase activity, guanosine triphosphate (GTP) binding, and guanosine triphosphatase (GTPase) activity. RESULTS: The disease was found to co-segregate with the LRRK2 N1437D mutation. Patients in the pedigree exhibited typical parkinsonism (age at onset: 54.0 ± 5.9 years). One affected family member - who had evidence of abnormal tau accumulation in the occipital lobe on tau PET imaging - developed PD dementia at follow-up. The mutation markedly increased LRRK2 kinase activity and promoted GTP binding, without affecting GTPase activity. CONCLUSIONS: This study describes the functional impact of a recently identified LRRK2 mutation, N1437D, that causes autosomal dominant PD in the Chinese population. Further research is necessary to investigate the contribution of this mutation to PD in multiple Asian populations.
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Enfermedad de Parkinson , Humanos , Pueblos del Este de Asia , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , Guanosina Trifosfato/metabolismo , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Mutación/genética , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patologíaRESUMEN
Senescence is a cellular response characterized by cells irreversibly stopping dividing and entering a state of permanent growth arrest. One of the underlying pathophysiological causes of senescence is the oxidative stress-induced damage, indicating that eliminating the reactive oxygen and nitrogen species (RONS) may be beneficial to prevent and/or alleviate senescence. Herein, we developed ultra-small polydopamine nanoparticles (UPDA NPs) with superoxide dismutase (SOD)/catalase (CAT) enzyme-mimic activities, featuring broad-spectrum RONS-scavenging capability for inducing cytoprotective effects against RONS-mediated damage. The engineered UPDA NPs can restore senescence-related renal function, tissue homeostasis, fur density, and motor ability in mice, potentially associated with the regulation of multiple genes involved in lipid metabolism, mitochondrial function, energy homeostasis, telomerase activity, neuroprotection, and inflammatory responses. Importantly, the dietary UPDA NPs can enhance the antioxidant capacity, improve the climbing ability, and prolong the lifespan of Drosophila. Notably, UPDA NPs possess excellent biocompatibility stemming from the ultra-small size, ensuring quick clearance out of the body. These findings reveal that UPDA NPs can delay aging through reducing oxidative stress and provide a paradigm and practical strategy for treating senescence and senescence-related diseases.
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Enhanced appetite occurs as a means of behavioral thermoregulation at low temperature. Neural circuitry mediating this crosstalk between behavioral thermoregulation and energy homeostasis remains to be elucidated. We find that the hypothalamic orexigenic agouti-related neuropeptide (AgRP) neurons in the arcuate nucleus (ARC) are profoundly activated by cold exposure. The calcium signals in ARCAgRP neurons display an immediate-response pattern in response to cold stimulation. Cold-responsive neurons in the medial preoptic area (mPOA) make excitatory synapses onto ARCAgRP neurons. Inhibition of either ARCAgRP neurons or ARC-projecting mPOA neurons attenuates cold-evoked feeding, while activation of the mPOA-to-ARC projection increases food intake. These findings reveal an mPOA-ARCAgRP neural pathway that modulates cold-evoked feeding behavior.
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Proteína Relacionada con Agouti/metabolismo , Núcleo Arqueado del Hipotálamo/fisiología , Frío , Conducta Alimentaria , Vías Nerviosas/fisiología , Área Preóptica/fisiología , Animales , Ratones Endogámicos C57BL , Neuronas/metabolismo , Sinapsis/metabolismoRESUMEN
BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease. One of the pathologies of AD is the accumulation of amyloid-ß (Aß) to form senile plaques, leading to a decline in cognitive ability and a lack of learning and memory. However, the cause leading to Aß aggregation is not well understood. Dendritic cell factor 1 (Dcf1) shows a high expression in the entorhinal cortex neurons and neurofibrillary tangles in AD patients. OBJECTIVE: Our goal is to investigate the effect of Dcf1 on Aß aggregation and memory deficits in AD development. METHODS: The mouse and Drosophila AD model were used to test the expression and aggregation of Aß, senile plaque formation, and pathological changes in cognitive behavior during dcf1 knockout and expression. We finally explored possible drug target effects through intracerebroventricular delivery of Dcf1 antibodies. RESULTS: Deletion of Dcf1 resulted in decreased Aß42 level and deposition, and rescued AMPA Receptor (GluA2) levels in the hippocampus of APP-PS1-AD mice. In Aß42 AD Drosophila, the expression of Dcf1 in Aß42 AD flies aggravated the formation and accumulation of senile plaques, significantly reduced its climbing ability and learning-memory. Data analysis from all 20 donors with and without AD patients aged between 80 and 90 indicated a high-level expression of Dcf1 in the temporal neocortex. Dcf1 contributed to Aß aggregation by UV spectroscopy assay. Intracerebroventricular delivery of Dcf1 antibodies in the hippocampus reduced the area of senile plaques and reversed learning and memory deficits in APP-PS1-AD mice. CONCLUSION: Dcf1 causes Aß-plaque accumulation, inhibiting dcf1 expression could potentially offer therapeutic avenues.
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Péptidos beta-Amiloides/metabolismo , Hipocampo/metabolismo , Proteínas de la Membrana/genética , Trastornos de la Memoria/genética , Proteínas del Tejido Nervioso/genética , Agregación Patológica de Proteínas/genética , Anciano de 80 o más Años , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Condicionamiento Clásico/fisiología , Drosophila melanogaster , Hipocampo/patología , Humanos , Aprendizaje/fisiología , Proteínas de la Membrana/metabolismo , Memoria/fisiología , Trastornos de la Memoria/metabolismo , Ratones , Ratones Noqueados , Ratones Transgénicos , Proteínas del Tejido Nervioso/metabolismo , Agregación Patológica de Proteínas/metabolismo , Agregación Patológica de Proteínas/patología , Receptores AMPA/metabolismoRESUMEN
Alzheimer's disease (AD) is a progressive neurodegenerative disorder. The generation of amyloid-ß from the amyloid precursor protein (APP) C-terminal fragment (C99) by γ-secretase cleavage is one of the main pathological mechanisms of AD. Dendritic cell factor 1 (Dcf1) is a membrane protein that was previously found to play a role in the development of AD. Bioinformatic analysis of AD patients indicated that Dcf1 may affect γ-secretase. In this study, we confirmed that Dcf1 attenuates the cleavage of C99 in vivo and in vitro. By using C99 transgenic AD drosophila, we found that Dcf1 reduces the cleavage of C99 by γ-secretase using Dcf1 overexpression. The climbing ability and lifespan of C99 drosophila were significantly increased, while learning and memory were also enhanced with Dcf1 expression. Increased levels of C99 protein in Dcf1-AD drosophila reveals inhibition of C99 cleavage by Dcf1 in vivo. Dcf1 inhibition of γ-secretase was further confirmed in vitro. These results provide a potential therapeutic target for the treatment of AD and also propose a new mechanism for understanding the occurrence of AD.
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Precursor de Proteína beta-Amiloide/metabolismo , Drosophila , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Fragmentos de Péptidos/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Animales Modificados Genéticamente , Modelos Animales de Enfermedad , Drosophila/genética , Drosophila/fisiología , Humanos , Longevidad , Proteínas de la Membrana/genética , Memoria , Proteínas del Tejido Nervioso/genética , Fragmentos de Péptidos/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Regulación hacia ArribaRESUMEN
Understanding the mechanisms of activity-dependent gene transcription underlying adaptive behaviors is challenging at neuronal-subtype resolution. Using cell-type specific molecular analysis in agouti-related peptide (AgRP) neurons, we reveal that the profound hunger-induced transcriptional changes greatly depend on plant homeodomain finger protein 6 (PHF6), a transcriptional repressor enriched in AgRP neurons. Loss of PHF6 in the satiated mice results in a hunger-state-shifting transcriptional profile, while hunger fails to further induce a rapid and robust activity-dependent gene transcription in PHF6-deficient AgRP neurons. We reveal that PHF6 binds to the promoters of a subset of immediate-early genes (IEGs) and that this chromatin binding is dynamically regulated by hunger state. Depletion of PHF6 decreases hunger-driven feeding motivation and makes the mice resistant to body weight gain under repetitive fasting-refeeding conditions. Our work identifies a neuronal subtype-specific transcriptional repressor that modulates transcriptional profiles in different nutritional states and enables adaptive eating behavior.
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Cromatina/metabolismo , Redes Reguladoras de Genes/genética , Hambre/fisiología , Neuronas/metabolismo , Proteínas Represoras/metabolismo , Proteína Relacionada con Agouti/metabolismo , Animales , Dieta , Regulación hacia Abajo/genética , Conducta Alimentaria , Ontología de Genes , Genes Inmediatos-Precoces , Hipotálamo/metabolismo , Ratones Endogámicos C57BL , Motivación , Regiones Promotoras Genéticas/genética , Unión Proteica , Proteínas Represoras/genética , Respuesta de Saciedad , Aumento de PesoRESUMEN
Parkinson's disease (PD) is a common neurodegenerative disease associated with the progressive loss of dopaminergic neurons in the substantia nigra. Proteinaceous depositions of alpha-synuclein (α-syn) and its mutations, A30P and A53T, are one important characteristic of PD. However, little is known about their aggregation and degradation mechanisms. Dendritic cell factor 1 (DCF1) is a membrane protein that plays important roles in nerve development in mouse. In this study, we aimed to show that DCF1 overexpression in a PD Drosophila model significantly ameliorates impaired locomotor behavior in third instar larvae and normalizes neuromuscular junction growth. Furthermore, climbing ability also significantly increased in adult PD Drosophila. More importantly, the lifespan dramatically extended by an average of approximately 23%, and surprisingly, DCF1 could prevent α-syn-induced dopaminergic neuron loss by aggregating α-syn in the dorsomedial region of Drosophila. Mechanistically, we confirmed that DCF1 could degrade α-syn both in vivo and in vitro. Our findings revealed an important role of DCF1 in PD process and may provide new potential strategies for developing drugs to treat neurodegenerative diseases.
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Proteínas de la Membrana/fisiología , Proteínas del Tejido Nervioso/fisiología , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/genética , Proteolisis , alfa-Sinucleína/metabolismo , Animales , Modelos Animales de Enfermedad , Drosophila , Expresión Génica , Células HEK293 , Humanos , Proteínas de la Membrana/genética , Actividad Motora , Mutación , Proteínas del Tejido Nervioso/genética , Unión Neuromuscular/crecimiento & desarrollo , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/fisiopatología , alfa-Sinucleína/genéticaRESUMEN
Optogenetics play a significant role in neuroscientific research by providing a tool for understanding neural circuits and brain functions. Natronomonas pharaonis halorhodopsin (NpHR) actively pumps chloride ions into the cells and hyperpolarizes neuronal membranes in response to yellow light. In this study, we generated transgenic Drosophila expressing NpHR under the control of the Gal4/UAS system and virus-infected mice expressing NpHR to explore the effect of dendritic cell factor 1 (Dcf1) on the behavior mediated by the mushroom body in Drosophila and the dentate gyrus (DG) in mice. Study of optogenetic behavior showed that NpHR suppressed the behavior in Drosophila larvae and mice, whereas Dcf1 rescued this suppression. These results suggest that Dcf1 plays an important role in behavior induced by the mushroom body and the hippocampus and provides novel insights into their functions. J. Cell. Biochem. 118: 4210-4215, 2017. © 2017 Wiley Periodicals, Inc.