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1.
Neurobiol Dis ; 174: 105878, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36183947

RESUMO

The striatum receives abundant glutamatergic afferents from the cortex and thalamus. These inputs play a major role in the functions of the striatal neurons in normal conditions, and are significantly altered in pathological states, such as Parkinson's disease. This review summarizes the current knowledge of the connectivity of the corticostriatal and thalamostriatal pathways, with emphasis on the most recent advances in the field. We also discuss novel findings regarding structural changes in cortico- and thalamostriatal connections that occur in these connections as a consequence of striatal loss of dopamine in parkinsonism.


Assuntos
Doença de Parkinson , Tálamo , Humanos , Tálamo/patologia , Corpo Estriado/patologia , Córtex Cerebral/patologia , Neurônios/patologia , Doença de Parkinson/patologia , Vias Neurais/patologia
2.
EMBO Mol Med ; 14(7): e15851, 2022 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-35670111

RESUMO

Aberrant localization of proteins to mitochondria disturbs mitochondrial function and contributes to the pathogenesis of Huntington's disease (HD). However, the crucial factors and the molecular mechanisms remain elusive. Here, we found that heat shock transcription factor 1 (HSF1) accumulates in the mitochondria of HD cell models, a YAC128 mouse model, and human striatal organoids derived from HD induced pluripotent stem cells (iPSCs). Overexpression of mitochondria-targeting HSF1 (mtHSF1) in the striatum causes neurodegeneration and HD-like behavior in mice. Mechanistically, mtHSF1 facilitates mitochondrial fission by activating dynamin-related protein 1 (Drp1) phosphorylation at S616. Moreover, mtHSF1 suppresses single-stranded DNA-binding protein 1 (SSBP1) oligomer formation, which results in mitochondrial DNA (mtDNA) deletion. The suppression of HSF1 mitochondrial localization by DH1, a unique peptide inhibitor, abolishes HSF1-induced mitochondrial abnormalities and ameliorates deficits in an HD animal model and human striatal organoids. Altogether, our findings describe an unsuspected role of HSF1 in contributing to mitochondrial dysfunction, which may provide a promising therapeutic target for HD.


Assuntos
Fatores de Transcrição de Choque Térmico , Doença de Huntington , Animais , Corpo Estriado/patologia , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Modelos Animais de Doenças , Fatores de Transcrição de Choque Térmico/metabolismo , Doença de Huntington/patologia , Camundongos , Mitocôndrias/metabolismo
3.
J Hazard Mater ; 430: 128459, 2022 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-35739658

RESUMO

With the prevalence of nanoplastics in daily life, human exposure is inevitable. However, whether and how nanoplastics cause neurotoxicity in humans remains obscure. Herein, we conducted a 28-day repeated dose oral toxicity study in C57BL/6 J mice exposed to 0.25-250 mg/kg body weight (BW) polystyrene nanoplastics (PS-NPs, 50 nm). We revealed that PS-NP-caused Parkinson's disease (PD)-like neurodegeneration in mice by multiple approaches. Furthermore, a single-nucleus RNA sequencing of 62,843 brain nuclei unearthed PS-NP-induced cell-specific responses in the mouse brains. These disturbed responses among various brain cells were primarily linked with energy metabolism disorder and mitochondrial dysfunction in all brain cells, and especially in excitatory neurons, accompanied by inflammatory turbulence in astrocytes and microglia, dysfunction of proteostasis and synaptic-function regulation in astrocytes, oligodendrocytes, and endotheliocytes. These responses may synergize in PS-NP-motivated PD-like neurodegeneration pathogenesis. Moreover, we verified these single-nucleus transcriptomics findings on different brain regions and found that PS-NPs potentially caused PD-like neurodegeneration primarily by causing energy metabolism disorder in the substantia nigra pars compacta (SNc) and striatum. This manifested as decreases in adenosine triphosphate (ATP) content and expression levels of ATP-associated genes and proteins. Given nanoplastics' inevitable and growing exposure risks to humans, the neurological health risks of nanoplastic exposure warrant serious consideration.


Assuntos
Doença de Parkinson , Trifosfato de Adenosina/metabolismo , Animais , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Modelos Animais de Doenças , Metabolismo Energético , Camundongos , Camundongos Endogâmicos C57BL , Microplásticos , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Poliestirenos/metabolismo , Poliestirenos/toxicidade , Transcriptoma
6.
Mov Disord ; 37(10): 2057-2065, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35765711

RESUMO

BACKGROUND: Parkinson's disease (PD) exhibits a high prevalence of dementia as disease severity and duration progress. Focused ultrasound (FUS) has been applied for transient blood-brain barrier (BBB) opening of cortical regions in neurodegenerative disorders. The striatum is a primary target for delivery of putative therapeutic agents in PD. OBJECTIVE: Here, we report a prospective, single-arm, nonrandomized, proof-of-concept, phase I clinical trial (NCT03608553 amended) in PD with dementia to test the safety and feasibility of striatal BBB opening in PD patients. METHODS: Seven PD patients with cognitive impairment were treated for BBB opening in the posterior putamen. This was performed in two sessions separated by 2 to 4 weeks, where the second session included bilateral putamina opening in 3 patients. Primary outcome measures included safety and feasibility of focal striatal BBB opening. Changes in motor and cognitive functions, magnetic resonance imaging (MRI), 18 F-fluorodopa (FDOPA), and ß-amyloid PET (positron emission tomography) images were determined. RESULTS: The procedure was feasible and well tolerated, with no serious adverse events. No neurologically relevant change in motor and cognitive (battery of neuropsychological tests) functions was recognized at follow-up. MRI revealed putamen BBB closing shortly after treatment (24 hours to 14 days) and ruled out hemorrhagic and ischemic lesions. There was a discrete but significant reduction in ß-amyloid uptake in the targeted region and no change in FDOPA PET. CONCLUSIONS: These initial results indicate that FUS-mediated striatal BBB opening is feasible and safe and therefore could become an effective tool to facilitate the delivery of putative neurorestorative molecules in PD. © 2022 International Parkinson and Movement Disorder Society.


Assuntos
Doença de Alzheimer , Demência , Doença de Parkinson , Peptídeos beta-Amiloides , Barreira Hematoencefálica , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/patologia , Di-Hidroxifenilalanina/análogos & derivados , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/patologia , Estudos Prospectivos
7.
J Huntingtons Dis ; 11(1): 25-33, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35253772

RESUMO

BACKGROUND: In recent years the functions of astrocytes have shifted from conventional supportive roles to also include active roles in altering synapses and engulfment of cellular debris. Recent studies have implicated astrocytes in both protective and pathogenic roles impacting Huntington's disease (HD) progression. OBJECTIVE: The goal of this study is to determine if phagocytosis of cellular debris is compromised in HD striatal astrocytes. METHODS: Primary adult astrocytes were derived from two HD mouse models; the fast-progressing R6/2 and slower progressing Q175. With the use of laser nanosurgery, a single astrocyte was lysed within an astrocyte network. The phagocytic response of astrocytes was observed with phase contrast and by fluorescence microscopy for GFP-LC3 transiently transfected cells. RESULTS: Astrocyte phagocytosis was significantly diminished in primary astrocytes, consistent with the progression of HD in R6/2 and Q175 mouse models. This was defined by the number of astrocytes responding via phagocytosis and by the average number of vesicles formed per cell. GFP-LC3 was found to increasingly localize to phagocytic vesicles over a 20-min imaging period, but not in HD mice, suggesting the involvement of LC3 in astrocyte phagocytosis. CONCLUSION: We demonstrate a progressive decrease in LC3-associated phagocytosis in HD mouse striatal astrocytes.


Assuntos
Doença de Huntington , Animais , Astrócitos/patologia , Corpo Estriado/patologia , Modelos Animais de Doenças , Doença de Huntington/patologia , Camundongos , Camundongos Transgênicos , Fagocitose
8.
Neuropathol Appl Neurobiol ; 48(5): e12812, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35274336

RESUMO

AIMS: The striatum is mainly composed of projection neurons. It also contains interneurons, which modulate and control striatal output. The aim of the present study was to assess the percentages of projection neurons and interneuron populations in the striatum of control monkeys and of parkinsonian monkeys. METHODS: Unbiased stereology was used to estimate the volume density of every neuron population in the caudate, putamen and ventral striatum of control monkeys and of monkeys treated with MPTP, which results in striatal dopamine depletion. The various neuron population phenotypes were identified by immunohistochemistry. All analyses were performed within the same subjects using similar processing and analysis parameters, thus allowing for reliable data comparisons. RESULTS: In control monkeys, the projection neurons, which express the dopamine-and-cAMP-regulated-phosphoprotein, 32-KDa (DARPP-32), were the most abundant: ~86% of the total neurons counted. The interneurons accounted for the remaining 14%. Among the interneurons, those expressing calretinin were the most abundant (Cr+: ~57%; ~8% of the total striatal neurons counted), followed those expressing Parvalbumin (Pv+: ~18%; 2.6%), dinucleotide phosphate-diaphorase (NADPH+: ~13%; 1.8%), choline acetyltransferase (ChAT+: ~11%; 1.5%) and tyrosine hydroxylase (TH+: ~0.5%; 0.1%). No significant changes in volume densities occurred in any population following dopamine depletion, except for the TH+ interneurons, which increased in parkinsonian non-symptomatic monkeys and even more in symptomatic monkeys. CONCLUSIONS: These data are relevant for translational studies targeting specific neuron populations of the striatum. The fact that dopaminergic denervation does not cause neuron loss in any population has potential pathophysiological implications.


Assuntos
Corpo Estriado , Dopamina , Interneurônios , Neurônios , Transtornos Parkinsonianos , Animais , Corpo Estriado/citologia , Corpo Estriado/patologia , Haplorrinos , Interneurônios/citologia , Neurônios/citologia , Transtornos Parkinsonianos/fisiopatologia
9.
Int J Mol Sci ; 23(4)2022 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-35216408

RESUMO

Autism spectrum disorders (ASD) are complex conditions that stem from a combination of genetic, epigenetic and environmental influences during early pre- and postnatal childhood. The review focuses on the cerebellum and the striatum, two structures involved in motor, sensory, cognitive and social functions altered in ASD. We summarize clinical and fundamental studies highlighting the importance of these two structures in ASD. We further discuss the relation between cellular and molecular alterations with the observed behavior at the social, cognitive, motor and gait levels. Functional correlates regarding neuronal activity are also detailed wherever possible, and sexual dimorphism is explored pointing to the need to apprehend ASD in both sexes, as findings can be dramatically different at both quantitative and qualitative levels. The review focuses also on a set of three recent papers from our laboratory where we explored motor and gait function in various genetic and environmental ASD animal models. We report that motor and gait behaviors can constitute an early and quantitative window to the disease, as they often correlate with the severity of social impairments and loss of cerebellar Purkinje cells. The review ends with suggestions as to the main obstacles that need to be surpassed before an appropriate management of the disease can be proposed.


Assuntos
Transtorno do Espectro Autista/patologia , Cerebelo/patologia , Corpo Estriado/patologia , Animais , Humanos , Modelos Animais , Neurônios/patologia , Células de Purkinje/patologia
10.
Proc Natl Acad Sci U S A ; 119(5)2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35086928

RESUMO

The CAG expansion of huntingtin (mHTT) associated with Huntington disease (HD) is a ubiquitously expressed gene, yet it prominently damages the striatum and cortex, followed by widespread peripheral defects as the disease progresses. However, the underlying mechanisms of neuronal vulnerability are unclear. Previous studies have shown that SUMO1 (small ubiquitin-like modifier-1) modification of mHtt promotes cellular toxicity, but the in vivo role and functions of SUMO1 in HD pathogenesis are unclear. Here, we report that SUMO1 deletion in Q175DN HD-het knockin mice (HD mice) prevented age-dependent HD-like motor and neurological impairments and suppressed the striatal atrophy and inflammatory response. SUMO1 deletion caused a drastic reduction in soluble mHtt levels and nuclear and extracellular mHtt inclusions while increasing cytoplasmic mHtt inclusions in the striatum of HD mice. SUMO1 deletion promoted autophagic activity, characterized by augmented interactions between mHtt inclusions and a lysosomal marker (LAMP1), increased LC3B- and LAMP1 interaction, and decreased interaction of sequestosome-1 (p62) and LAMP1 in DARPP-32-positive medium spiny neurons in HD mice. Depletion of SUMO1 in an HD cell model also diminished the mHtt levels and enhanced autophagy flux. In addition, the SUMOylation inhibitor ginkgolic acid strongly enhanced autophagy and diminished mHTT levels in human HD fibroblasts. These results indicate that SUMO is a critical therapeutic target in HD and that blocking SUMO may ameliorate HD pathogenesis by regulating autophagy activities.


Assuntos
Autofagia/fisiologia , Doença de Huntington/metabolismo , Proteína SUMO-1/metabolismo , Animais , Morte Celular Autofágica/fisiologia , Encéfalo/patologia , Corpo Estriado/patologia , Modelos Animais de Doenças , Humanos , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doença de Huntington/genética , Doença de Huntington/fisiopatologia , Glicoproteínas de Membrana Associadas ao Lisossomo/metabolismo , Lisossomos/patologia , Camundongos , Camundongos Transgênicos , Neostriado/patologia , Neurônios/patologia , Proteína SUMO-1/genética , Proteína SUMO-1/fisiologia
11.
Molecules ; 27(2)2022 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-35056822

RESUMO

Since the discovery of α-synuclein as the major component in Lewy bodies, research into this protein in the context of Parkinson's disease pathology has been exponential. Cannabinoids are being investigated as potential therapies for Parkinson's disease from numerous aspects, but still little is known about the links between the cannabinoid system and the pathogenic α-synuclein protein; understanding these links will be necessary if cannabinoid therapies are to reach the clinic in the future. Therefore, the aim of this study was to investigate the time-course of alterations in components of the endocannabinoid system after viral-mediated α-synuclein overexpression in the rat brain. Rats were given unilateral intranigral injections of AAV-GFP or AAV-α-synuclein and sacrificed 4, 8 and 12 weeks later for qRT-PCR and liquid chromatography-mass spectrometry analyses of the endocannabinoid system, in addition to histological visualization of α-synuclein expression along the nigrostriatal pathway. As anticipated, intranigral delivery of AAV-α-synuclein induced widespread overexpression of human α-synuclein in the nigrostriatal pathway, both at the mRNA level and the protein level. However, despite this profound α-synuclein overexpression, we detected no differences in CB1 or CB2 receptor expression in the nigrostriatal pathway; however, interestingly, there was a reduction in the expression of neuroinflammatory markers. Furthermore, there was a reduction in the levels of the endocannabinoid 2-AG and the related lipid immune mediator OEA at week 12 post-surgery, indicating that α-synuclein overexpression triggers dysregulation of the endocannabinoid system. Although this research does show that the endocannabinoid system is impacted by α-synuclein, further research is necessary to more comprehensively understand the link between the cannabinoid system and the α-synuclein aspect of Parkinson's disease pathology in order for cannabinoid-based therapies to be feasible for the treatment of this disease in the coming years.


Assuntos
Corpo Estriado/patologia , Dependovirus/genética , Endocanabinoides/metabolismo , Substância Negra/patologia , alfa-Sinucleína/metabolismo , Animais , Corpo Estriado/metabolismo , Feminino , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/genética , Receptor CB2 de Canabinoide/metabolismo , Substância Negra/metabolismo , Fatores de Tempo , alfa-Sinucleína/administração & dosagem , alfa-Sinucleína/genética
12.
Int J Mol Sci ; 23(1)2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-35008995

RESUMO

The present study investigated the effects of interleukin (IL)-4 on striatal neurons in lipopolysaccharide (LPS)-injected rat striatum in vivo. Either LPS or PBS as a control was unilaterally injected into the striatum, and brain tissues were processed for immunohistochemical and Nissl staining or for hydroethidine histochemistry at the indicated time points after LPS injection. Analysis by NeuN and Nissl immunohistochemical staining showed a significant loss of striatal neurons at 1, 3, and 7 days post LPS. In parallel, IL-4 immunoreactivity was upregulated as early as 1 day, reached a peak at 3 days, and was sustained up to 7 days post LPS. Increased levels of IL-4 immunoreactivity were exclusively detected in microglia/macrophages, but not in neurons nor astrocytes. The neutralizing antibody (NA) for IL-4 significantly protects striatal neurons against LPS-induced neurotoxicity in vivo. Accompanying neuroprotection, IL-4NA inhibited activation of microglia/macrophages, production of reactive oxygen species (ROS), ROS-derived oxidative damage and nitrosative stress, and produced polarization of microglia/macrophages shifted from M1 to M2. These results suggest that endogenous IL-4 expressed in LPS-activated microglia/macrophages contributes to striatal neurodegeneration in which oxidative/nitrosative stress and M1/M2 polarization are implicated.


Assuntos
Interleucina-4/metabolismo , Lipopolissacarídeos/efeitos adversos , Microglia/imunologia , Microglia/metabolismo , Estresse Oxidativo , Degeneração Estriatonigral/etiologia , Degeneração Estriatonigral/metabolismo , Animais , Biomarcadores , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Imuno-Histoquímica , Lipopolissacarídeos/imunologia , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Microglia/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Degeneração Estriatonigral/patologia
13.
Mol Neurobiol ; 59(4): 2532-2551, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35091961

RESUMO

While the genetic cause of Huntington disease (HD) is known since 1993, still no cure exists. Therapeutic development would benefit from a method to monitor disease progression and treatment efficacy, ideally using blood biomarkers. Previously, HD-specific signatures were identified in human blood representing signatures in human brain, showing biomarker potential. Since drug candidates are generally first screened in rodent models, we aimed to identify HD signatures in blood and brain of YAC128 HD mice and compare these with previously identified human signatures. RNA sequencing was performed on blood withdrawn at two time points and four brain regions from YAC128 and control mice. Weighted gene co-expression network analysis was used to identify clusters of co-expressed genes (modules) associated with the HD genotype. These HD-associated modules were annotated via text-mining to determine the biological processes they represented. Subsequently, the processes from mouse blood were compared with mouse brain, showing substantial overlap, including protein modification, cell cycle, RNA splicing, nuclear transport, and vesicle-mediated transport. Moreover, the disease-associated processes shared between mouse blood and brain were highly comparable to those previously identified in human blood and brain. In addition, we identified HD blood-specific pathology, confirming previous findings for peripheral pathology in blood. Finally, we identified hub genes for HD-associated blood modules and proposed a strategy for gene selection for development of a disease progression monitoring panel.


Assuntos
Fenômenos Biológicos , Doença de Huntington , Animais , Encéfalo/metabolismo , Corpo Estriado/patologia , Modelos Animais de Doenças , Progressão da Doença , Proteína Huntingtina/metabolismo , Doença de Huntington/patologia , Camundongos , Camundongos Transgênicos , Transcriptoma/genética
14.
Hum Brain Mapp ; 43(1): 352-372, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34498337

RESUMO

Schizophrenia is associated with widespread alterations in subcortical brain structure. While analytic methods have enabled more detailed morphometric characterization, findings are often equivocal. In this meta-analysis, we employed the harmonized ENIGMA shape analysis protocols to collaboratively investigate subcortical brain structure shape differences between individuals with schizophrenia and healthy control participants. The study analyzed data from 2,833 individuals with schizophrenia and 3,929 healthy control participants contributed by 21 worldwide research groups participating in the ENIGMA Schizophrenia Working Group. Harmonized shape analysis protocols were applied to each site's data independently for bilateral hippocampus, amygdala, caudate, accumbens, putamen, pallidum, and thalamus obtained from T1-weighted structural MRI scans. Mass univariate meta-analyses revealed more-concave-than-convex shape differences in the hippocampus, amygdala, accumbens, and thalamus in individuals with schizophrenia compared with control participants, more-convex-than-concave shape differences in the putamen and pallidum, and both concave and convex shape differences in the caudate. Patterns of exaggerated asymmetry were observed across the hippocampus, amygdala, and thalamus in individuals with schizophrenia compared to control participants, while diminished asymmetry encompassed ventral striatum and ventral and dorsal thalamus. Our analyses also revealed that higher chlorpromazine dose equivalents and increased positive symptom levels were associated with patterns of contiguous convex shape differences across multiple subcortical structures. Findings from our shape meta-analysis suggest that common neurobiological mechanisms may contribute to gray matter reduction across multiple subcortical regions, thus enhancing our understanding of the nature of network disorganization in schizophrenia.


Assuntos
Tonsila do Cerebelo/patologia , Corpo Estriado/patologia , Hipocampo/patologia , Neuroimagem , Esquizofrenia/patologia , Tálamo/patologia , Tonsila do Cerebelo/diagnóstico por imagem , Corpo Estriado/diagnóstico por imagem , Hipocampo/diagnóstico por imagem , Humanos , Estudos Multicêntricos como Assunto , Esquizofrenia/diagnóstico por imagem , Tálamo/diagnóstico por imagem
15.
Brain Pathol ; 32(2): e13036, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34806235

RESUMO

Misfolded α-synuclein spreads along anatomically connected areas through the brain, prompting progressive neurodegeneration of the nigrostriatal pathway in Parkinson's disease. To investigate the impact of early stage seeding and spreading of misfolded α-synuclein along with the nigrostriatal pathway, we studied the pathophysiologic effect induced by a single acute α-synuclein preformed fibrils (PFFs) inoculation into the midbrain. Further, to model the progressive vulnerability that characterizes the dopamine (DA) neuron life span, we used two cohorts of mice with different ages: 2-month-old (young) and 5-month-old (adult) mice. Two months after α-synuclein PFFs injection, we found that striatal DA release decreased exclusively in adult mice. Adult DA neurons showed an increased level of pathology spreading along with the nigrostriatal pathway accompanied with a lower volume of α-synuclein deposition in the midbrain, impaired neurotransmission, rigid DA terminal composition, and less microglial reactivity compared with young neurons. Notably, preserved DA release and increased microglial coverage in the PFFs-seeded hemisphere coexist with decreased large-sized terminal density in young DA neurons. This suggests the presence of a targeted pruning mechanism that limits the detrimental effect of α-synuclein early spreading. This study suggests that the impact of the pathophysiology caused by misfolded α-synuclein spreading along the nigrostriatal pathway depends on the age of the DA network, reducing striatal DA release specifically in adult mice.


Assuntos
Doença de Parkinson , alfa-Sinucleína , Animais , Corpo Estriado/patologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Camundongos , Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismo
16.
Hum Brain Mapp ; 43(1): 341-351, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-32198905

RESUMO

Alterations in regional subcortical brain volumes have been investigated as part of the efforts of an international consortium, ENIGMA, to identify reliable neural correlates of major depressive disorder (MDD). Given that subcortical structures are comprised of distinct subfields, we sought to build significantly from prior work by precisely mapping localized MDD-related differences in subcortical regions using shape analysis. In this meta-analysis of subcortical shape from the ENIGMA-MDD working group, we compared 1,781 patients with MDD and 2,953 healthy controls (CTL) on individual measures of shape metrics (thickness and surface area) on the surface of seven bilateral subcortical structures: nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus. Harmonized data processing and statistical analyses were conducted locally at each site, and findings were aggregated by meta-analysis. Relative to CTL, patients with adolescent-onset MDD (≤ 21 years) had lower thickness and surface area of the subiculum, cornu ammonis (CA) 1 of the hippocampus and basolateral amygdala (Cohen's d = -0.164 to -0.180). Relative to first-episode MDD, recurrent MDD patients had lower thickness and surface area in the CA1 of the hippocampus and the basolateral amygdala (Cohen's d = -0.173 to -0.184). Our results suggest that previously reported MDD-associated volumetric differences may be localized to specific subfields of these structures that have been shown to be sensitive to the effects of stress, with important implications for mapping treatments to patients based on specific neural targets and key clinical features.


Assuntos
Tonsila do Cerebelo/patologia , Corpo Estriado/patologia , Transtorno Depressivo Maior/patologia , Hipocampo/patologia , Neuroimagem , Tálamo/patologia , Tonsila do Cerebelo/diagnóstico por imagem , Corpo Estriado/diagnóstico por imagem , Transtorno Depressivo Maior/diagnóstico por imagem , Hipocampo/diagnóstico por imagem , Humanos , Estudos Multicêntricos como Assunto , Tálamo/diagnóstico por imagem
17.
Nutr Neurosci ; 25(1): 100-109, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32093571

RESUMO

Background: Piperine (PIP) is a powerful anti-oxidant and anti-inflammatory alkaloid which has been widely used in the treatment of various pathological conditions. However, few studies have clearly discussed the protective effects and potential mechanism of PIP in different neurological diseases. The aim of this study was to investigate the neuroprotective effect of PIP against 3-nitropropioninc acid (3-NP) induced neurobehavioral, biochemical and histopathological alterations in animals.Methods: Adult male Wistar rats were randomly divided into three groups. Group 1, the vehicle administered control group, received normal saline (p.o.). Group 2 received 3-NP (20 mg/kg.b.wt., i.p.) for 4 consecutive days. Group 3 received PIP (10 mg/kg.b.wt., p.o.) twice daily for a period of 4 days, 30 min before and 6 h after the 3-NP injection. Upon termination of treatment schedule, behavioral experiments were performed to access the behavioral outcomes. The brain striatal tissue was used for the estimation of monoamine oxidase activity and serotonin level. In addition, astrocytes activation was observed by GFAP immunostaining.Results: Our results showed that 3-NP induced behavioral impairments are attenuated by PIP co-treatment. Next, the extent of neuronal loss and astrocytes activation was reduced in the striatal brain region in PIP treated rats. Finally, it was observed that PIP alleviated the behavioral, biochemical, immunohistochemical and histological alterations.Conclusion: The results of the current study reveal the neuroprotective competency of PIP against Huntington disease like symptoms in rats.


Assuntos
Alcaloides/uso terapêutico , Benzodioxóis/uso terapêutico , Doença de Huntington/tratamento farmacológico , Transtornos Mentais/prevenção & controle , Fármacos Neuroprotetores , Nitrocompostos/administração & dosagem , Piperidinas/uso terapêutico , Alcamidas Poli-Insaturadas/uso terapêutico , Propionatos/administração & dosagem , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/fisiologia , Comportamento Animal/efeitos dos fármacos , Corpo Estriado/química , Corpo Estriado/patologia , Modelos Animais de Doenças , Doença de Huntington/induzido quimicamente , Doença de Huntington/fisiopatologia , Masculino , Monoaminoxidase/análise , Neurônios/efeitos dos fármacos , Ratos , Ratos Wistar , Serotonina/análise
18.
Int J Mol Sci ; 22(23)2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34884469

RESUMO

Mouse models are frequently used to study Huntington's disease (HD). The onset and severity of neuronal and behavioral pathologies vary greatly between HD mouse models, which results from different huntingtin expression levels and different CAG repeat length. HD pathology appears to depend also on the strain background of mouse models. Thus, behavioral deficits of HD mice are more severe in the FVB than in the C57BL/6 background. Alterations in medium spiny neuron (MSN) morphology and function have been well documented in young YAC128 mice in the FVB background. Here, we tested the relevance of strain background for mutant huntingtin (mHTT) toxicity on the cellular level by investigating HD pathologies in YAC128 mice in the C57BL/6 background (YAC128/BL6). Morphology, spine density, synapse function and membrane properties were not or only subtly altered in MSNs of 12-month-old YAC128/BL6 mice. Despite the mild cellular phenotype, YAC128/BL6 mice showed deficits in motor performance. More pronounced alterations in MSN function were found in the HdhQ150 mouse model in the C57BL/6 background (HdhQ150/BL6). Consistent with the differences in HD pathology, the number of inclusion bodies was considerably lower in YAC128/BL6 mice than HdhQ150/BL6 mice. This study highlights the relevance of strain background for mHTT toxicity in HD mouse models.


Assuntos
Corpo Estriado/patologia , Proteína Huntingtina/genética , Doença de Huntington/patologia , Animais , Corpo Estriado/química , Modelos Animais de Doenças , Feminino , Doença de Huntington/genética , Doença de Huntington/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Sequências de Repetição em Tandem
19.
Int J Mol Sci ; 22(23)2021 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-34884918

RESUMO

PSD-95 (Dlg4) is an ionotropic glutamate receptor scaffolding protein essential in synapse stability and neurotransmission. PSD-95 levels are reduced during aging and in neurodegenerative diseases like Huntington's disease (HD), and it is believed to contribute to synaptic dysfunction and behavioral deficits. However, the mechanism responsible for PSD-95 dysregulation under these conditions is unknown. The Heat Shock transcription Factor 1 (HSF1), canonically known for its role in protein homeostasis, is also depleted in both aging and HD. Synaptic protein levels, including PSD-95, are influenced by alterations in HSF1 levels and activity, but the direct regulatory relationship between PSD-95 and HSF1 has yet to be determined. Here, we showed that HSF1 chronic or acute reduction in cell lines and mice decreased PSD-95 expression. Furthermore, Hsf1(+/-) mice had reduced PSD-95 synaptic puncta that paralleled a loss in thalamo-striatal excitatory synapses, an important circuit disrupted early in HD. We demonstrated that HSF1 binds to regulatory elements present in the PSD-95 gene and directly regulates PSD-95 expression. HSF1 DNA-binding on the PSD-95 gene was disrupted in an age-dependent manner in WT mice and worsened in HD cells and mice, leading to reduced PSD-95 levels. These results demonstrate a direct role of HSF1 in synaptic gene regulation that has important implications in synapse maintenance in basal and pathological conditions.


Assuntos
Envelhecimento/fisiologia , Proteína 4 Homóloga a Disks-Large/metabolismo , Fatores de Transcrição de Choque Térmico/metabolismo , Doença de Huntington/patologia , Sinapses/patologia , Envelhecimento/patologia , Animais , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Modelos Animais de Doenças , Proteína 4 Homóloga a Disks-Large/genética , Feminino , Regulação da Expressão Gênica , Fatores de Transcrição de Choque Térmico/genética , Humanos , Doença de Huntington/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Estudo de Prova de Conceito
20.
Int J Mol Sci ; 22(21)2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34768962

RESUMO

Parkinson's disease (PD) is a prevalent movement disorder characterized by the progressive loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). The 6-hydroxydopamine (6-OHDA) lesion is still one of the most widely used techniques for modeling Parkinson's disease (PD) in rodents. Despite commonly used in rats, it can be challenging to reproduce a similar lesion in mice. Moreover, there is a lack of characterization of the extent of behavioral deficits and of the neuronal loss/neurotransmitter system in unilateral lesion mouse models. In this study, we present an extensive behavioral and histological characterization of a unilateral intrastriatal 6-OHDA mouse model. Our results indicate significant alterations in balance and fine motor coordination, voluntary locomotion, and in the asymmetry's degree of forelimb use in 6-OHDA lesioned animals, accompanied by a decrease in self-care and motivational behavior, common features of depressive-like symptomatology. These results were accompanied by a decrease in tyrosine hydroxylase (TH)-labelling and dopamine levels within the nigrostriatal pathway. Additionally, we also identify a marked astrocytic reaction, as well as proliferative and reactive microglia in lesioned areas. These results confirm the use of unilateral intrastriatal 6-OHDA mice for the generation of a mild model of nigrostriatal degeneration and further evidences the recapitulation of key aspects of PD, thereby being suitable for future studies beholding new therapeutical interventions for this disease.


Assuntos
Corpo Estriado/efeitos dos fármacos , Corpo Estriado/fisiopatologia , Oxidopamina/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/fisiopatologia , Animais , Ansiedade/induzido quimicamente , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Corpo Estriado/patologia , Transtorno Depressivo/induzido quimicamente , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Destreza Motora/efeitos dos fármacos , Destreza Motora/fisiologia , Degeneração Neural/induzido quimicamente , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Neuroglia/efeitos dos fármacos , Neuroglia/patologia , Neuroglia/fisiologia , Transtornos Parkinsonianos/patologia , Fenótipo , Especificidade da Espécie , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Substância Negra/fisiopatologia , Fatores de Tempo
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