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1.
Brain Behav ; 14(7): e3607, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39010690

RESUMO

BACKGROUND: Pathologic perivascular spaces (PVS), the fluid-filled compartments surrounding brain vasculature, may underlie cognitive decline in Parkinson's disease (PD). However, whether this impacts specific cognitive domains has not been investigated. OBJECTIVES: This study examined the relationship of PVS volume at baseline with domain-specific and global cognitive change over 2 years in PD individuals. METHODS: A total of 39 individuals with PD underwent 3T T1w magnetic resonance imaging to determine PVS volume fraction (PVS volume normalized to total regional volume) within (i) centrum semiovale, (ii) prefrontal white matter (medial orbitofrontal, rostral middle frontal, and superior frontal), and (iii) basal ganglia. A neuropsychological battery included assessment of cognitive domains and global cognitive function at baseline and after 2 years. RESULTS: Higher basal ganglia PVS at baseline was associated with greater decline in attention, executive function, and global cognition scores. CONCLUSIONS: While previous reports have associated elevated PVS volume in the basal ganglia with decline in global cognition in PD, our findings show such decline may affect the attention and executive function domains.


Assuntos
Atenção , Gânglios da Base , Disfunção Cognitiva , Função Executiva , Imageamento por Ressonância Magnética , Doença de Parkinson , Humanos , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , Gânglios da Base/diagnóstico por imagem , Gânglios da Base/patologia , Gânglios da Base/fisiopatologia , Função Executiva/fisiologia , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Atenção/fisiologia , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/patologia , Sistema Glinfático/diagnóstico por imagem , Sistema Glinfático/patologia , Sistema Glinfático/fisiopatologia , Testes Neuropsicológicos , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Substância Branca/fisiopatologia
2.
Brain Behav ; 14(7): e3624, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39010704

RESUMO

INTRODUCTION: This study aims to evaluate the effects of sodium-glucose cotransporter 1 inhibitors (SGLT1i) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) on neurodegenerative disorders and to investigate the role of hemoglobin A1c (HbA1c) levels. METHODS: Utilizing drug target Mendelian randomization, we employed single nucleotide polymorphisms (SNPs) proximal to the SLC5A1 and SLC5A2 genes to analyze the influence of SGLT1i and SGLT2i on Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), frontotemporal dementia (FTD), Lewy body dementia (LBD), and amyotrophic lateral sclerosis (ALS), with type 2 diabetes (T2D) as a positive control. An additional analysis examined the impact of HbA1c levels on the same disorders. RESULTS: SGLT1i exhibited a significant association with decreased risk for ALS and MS. Conversely, SGLT2i were linked to an increased risk of AD, PD, and MS. Elevated HbA1c levels, independent of SGLT1 and SGLT2 effects, were associated with an increased risk of PD. Sensitivity analyses supported the robustness of these findings. CONCLUSION: Our study suggests that SGLT1i may confer protection against ALS and MS, whereas SGLT2i could elevate the risk of AD, PD, and MS. Additionally, elevated HbA1c levels emerged as a risk factor for PD. These findings underscore the importance of personalized approaches in the utilization of SGLT inhibitors, considering their varying impacts on the risks of neurodegenerative diseases.


Assuntos
Hemoglobinas Glicadas , Análise da Randomização Mendeliana , Doenças Neurodegenerativas , Polimorfismo de Nucleotídeo Único , Transportador 1 de Glucose-Sódio , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Doenças Neurodegenerativas/genética , Hemoglobinas Glicadas/metabolismo , Transportador 1 de Glucose-Sódio/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Transportador 2 de Glucose-Sódio/genética , Transportador 2 de Glucose-Sódio/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/tratamento farmacológico , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/tratamento farmacológico , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/genética
3.
PLoS One ; 19(7): e0307304, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39012877

RESUMO

BACKGROUND: Parkinson's Disease (PD) affects movement and cognition, and physiotherapy, particularly treadmill gait training, has potential in addressing movement dysfunctions in PD. However, treadmill training falls short in addressing cognitive aspects and adherence. Virtual reality (VR) and gamification can enhance motor and cognitive retraining and improve adherence. People with Parkinson's Disease (PWPD) have decreased motor skill learning efficiency, but tDCS can improve motor and cognitive learning. METHODS: 78 participants with PD will be randomly allocated in a 1:1:1 ratio to one of three groups: (1) treadmill + Gamified Virtual Reality Environment (GVRE) + tDCS training group; (2) treadmill + GVRE training group or (3) treadmill training group. Participants will follow a 6-week, 12-session treadmill gait training plan, gradually increasing session duration from 20 to 45 minutes. Participants in (1) and (2) will undergo a GVRE training protocol, with (1) also receiving tDCS for the first 20 minutes of each session. Assessments will occur at baseline, post-intervention, and at a 6-week follow-up. The primary outcome measure will be gait speed during single and dual-task performance. Secondary measures will include additional gait parameters, executive tests for cognitive performance, and clinical outcomes for disease stage, cognitive status, and physical condition. DISCUSSION: This randomized clinical trial presents an innovative neurorehabilitation protocol that aims to improve gait and cognition in PWPD. The study also examines how tDCS can enhance motor and cognitive training. Results could contribute to enhancing the motor and cognitive state of PWPD through a GVRE and tDCS-based neurorehabilitation protocol. TRIAL REGISTRATION: NCT05243394. 28/02/2024 -v3.2.


Assuntos
Terapia por Exercício , Doença de Parkinson , Estimulação Transcraniana por Corrente Contínua , Realidade Virtual , Humanos , Doença de Parkinson/reabilitação , Doença de Parkinson/terapia , Doença de Parkinson/fisiopatologia , Estimulação Transcraniana por Corrente Contínua/métodos , Terapia por Exercício/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Marcha/fisiologia , Idoso , Cognição
4.
Mol Biol Rep ; 51(1): 819, 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-39017801

RESUMO

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms, and is due to the degeneration of dopaminergic neurons. It is multifactorial, caused by genetic and environmental factors and currently has no definitive cure. We have investigated the protective effects of parthenolide (PTN), a compound with known anti-inflammatory and antioxidant properties, in an in vitro model of PD, that is induced by 6-OHDA, and that causes neurotoxicity in SH-SY5Y human neuroblastoma cells. METHODS AND RESULTS: SH-SY5Y cells were pretreated with PTN to assess its protective effects in 6-OHDA-induced cellular damage. Cell viability was measured using Alamar blue. Apoptosis was evaluated using an Annexin V-FITC/PI kit. Reactive oxygen species (ROS) levels were quantified, and expression levels of apoptotic markers (Bax, Bcl-2, p53) and NF-κB were analyzed via Western blotting and Quantitative real-time- (qRT-) PCR. We found that 6-OHDA reduced cell viability, that was inhibited significantly by pre-treatment with PTN (p < 0.05). Flow cytometry revealed that PTN reduced apoptosis induced by 6-OHDA. PTN also reduced the ROS levels raised by 6-OHDA (p < 0.05). Moreover, PTN decreased the expression of Bax, p53, NF-κB, and p-NF-κB that were increased by treatment with 6-OHDA. CONCLUSION: These findings indicate the potential beneficial effects of PTN in an in vitro model of PD via mitigating oxidative stress and inflammation, suggested PTN as a promising agent to be used for PD therapy, warranting further investigation in preclinical and clinical studies.


Assuntos
Apoptose , Sobrevivência Celular , NF-kappa B , Estresse Oxidativo , Oxidopamina , Doença de Parkinson , Espécies Reativas de Oxigênio , Sesquiterpenos , Estresse Oxidativo/efeitos dos fármacos , Humanos , Sesquiterpenos/farmacologia , NF-kappa B/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Oxidopamina/farmacologia , Fármacos Neuroprotetores/farmacologia , Antioxidantes/farmacologia
5.
ACS Chem Neurosci ; 15(14): 2623-2632, 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-38959406

RESUMO

Aggregated deposits of the protein α-synuclein and depleting levels of dopamine in the brain correlate with Parkinson's disease development. Treatments often focus on replenishing dopamine in the brain; however, the brain might not be the only site requiring attention. Aggregates of α-synuclein appear to accumulate in the gut years prior to the onset of any motor symptoms. Enteroendocrine cells (specialized gut epithelial cells) may be the source of intestinal α-synuclein, as they natively express this protein. Enteroendocrine cells are constantly exposed to gut bacteria and their metabolites because they border the gut lumen. These cells also express the dopamine metabolic pathway and form synapses with vagal neurons, which innervate the gut and brain. Through this connection, Parkinson's disease pathology may originate in the gut and spread to the brain over time. Effective therapeutics to prevent this disease progression are lacking due to a limited understanding of the mechanisms by which α-synuclein aggregation occurs in the gut. We previously proposed a gut bacterial metabolic pathway responsible for the initiation of α-synuclein aggregation that is dependent on the oxidation of dopamine. Here, we develop a new tool, a laser-induced graphene-based electrochemical sensor chip, to track α-synuclein aggregation and dopamine level over time. Using these sensor chips, we evaluated diet-derived catechols dihydrocaffeic acid and caffeic acid as potential inhibitors of α-synuclein aggregation. Our results suggest that these molecules inhibit dopamine oxidation. We also found that these dietary catechols inhibit α-synuclein aggregation in STC-1 enteroendocrine cells. These findings are critical next steps to reveal new avenues for targeted therapeutics to treat Parkinson's disease, specifically in the context of functional foods that may be used to reshape the gut environment.


Assuntos
Doença de Parkinson , alfa-Sinucleína , Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Humanos , Animais , Dopamina/metabolismo , Técnicas Eletroquímicas/métodos , Células Enteroendócrinas/metabolismo , Microbioma Gastrointestinal/fisiologia , Lasers
6.
Biomed Phys Eng Express ; 10(5)2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-38959873

RESUMO

Objective. Recent innovative neurostimulators allow recording local field potentials (LFPs) while performing motor tasks monitored by wearable sensors. Inertial sensors can provide quantitative measures of motor impairment in people with subthalamic nucleus deep brain stimulation. To the best of our knowledge, there is no validated method to synchronize inertial sensors and neurostimulators without an additional device. This study aims to define a new synchronization method to analyze disease-related brain activity patterns during specific motor tasks and evaluate how LFPs are affected by stimulation and medication.Approach. Fourteen male subjects treated with subthalamic nucleus deep brain stimulation were recruited to perform motor tasks in four different medication and stimulation conditions. In each condition, a synchronization protocol was performed consisting of taps on the implanted neurostimulator, which produces artifacts in the LFPs that a nearby inertial sensor can simultaneously record.Main results. In 64% of the recruited subjects, induced artifacts were detected at least in one condition. Among those subjects, 83% of the recordings could be synchronized offline analyzing LFPs and wearables data. The remaining recordings were synchronized by video analysis.Significance. The proposed synchronization method does not require an external system (e.g., TENS electrodes) and can be easily integrated into clinical practice. The procedure is simple and can be carried out in a short time. A proper and simple synchronization will also be useful to analyze subthalamic neural activity in the presence of specific events (e.g., freezing of gait events) to identify predictive biomarkers.


Assuntos
Estimulação Encefálica Profunda , Núcleo Subtalâmico , Humanos , Estimulação Encefálica Profunda/métodos , Estimulação Encefálica Profunda/instrumentação , Masculino , Pessoa de Meia-Idade , Artefatos , Processamento de Sinais Assistido por Computador , Adulto , Dispositivos Eletrônicos Vestíveis , Doença de Parkinson/terapia , Doença de Parkinson/fisiopatologia , Encéfalo , Idoso
7.
Rev Invest Clin ; 76(3): 159-169, 2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-39025496

RESUMO

Background: Immunomodulatory drugs and immunotherapies are being evaluated in clinical trials for the treatment of neuroinflammation, as the latter is an essential mechanism for the development and progression of Parkinson's disease. Objective: The objective of the study is to review recent evidence on the evaluation of immunomodulators in randomized controlled clinical trials measuring improvement of motor symptoms. Methods: A meta-analysis of Movement Disorder Society-Unified Parkinson's disease Rating Scale (MDS-UPDRS III) scores extracted from seven articles selected after an online search of PubMed, Cochrane Library, and Clarivate's Web of Science for randomized controlled clinical trials published between 2000 and July 2023 was performed. The selected articles reported clinical trials evaluating the effects of specific immunomodulators or treatments with known effects on the immune system and inflammation. MDS-UPDRS III scores were reported in these studies, and the results of the placebo groups were compared with those of the treatment groups. Results: A total of 590 patients treated with immunomodulators and 622 patients treated with placebo were included. A test for heterogeneity yielded an I2 value > 50%. The mean standard difference for change in MDS-UPDR III score was -0.46 (CI [95%] = -0.90 - -0.02, p < 0.01). No significant differences were found in the change in mean MDS-UPDR III score between the treatment and placebo groups; however, two studies showed a trend toward separation from the mean. Conclusion: The immunomodulatory treatments included in this study showed no efficacy in improving motor symptoms in Parkinson's disease patients. Further clinical trials with larger patient populations are needed.


Assuntos
Agentes de Imunomodulação , Doença de Parkinson , Ensaios Clínicos Controlados Aleatórios como Assunto , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/terapia , Humanos , Agentes de Imunomodulação/administração & dosagem , Agentes de Imunomodulação/uso terapêutico , Agentes de Imunomodulação/farmacologia , Imunomodulação , Fatores Imunológicos/uso terapêutico , Fatores Imunológicos/administração & dosagem , Imunoterapia/métodos
8.
BMJ ; 386: e078341, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38986549

RESUMO

OBJECTIVES: To assess the clinical effectiveness of two speech and language therapy approaches versus no speech and language therapy for dysarthria in people with Parkinson's disease. DESIGN: Pragmatic, UK based, multicentre, three arm, parallel group, unblinded, randomised controlled trial. SETTING: The speech and language therapy interventions were delivered in outpatient or home settings between 26 September 2016 and 16 March 2020. PARTICIPANTS: 388 people with Parkinson's disease and dysarthria. INTERVENTIONS: Participants were randomly assigned to one of three groups (1:1:1): 130 to Lee Silverman voice treatment (LSVT LOUD), 129 to NHS speech and language therapy, and 129 to no speech and language therapy. LSVT LOUD consisted of four, face-to-face or remote, 50 min sessions each week delivered over four weeks. Home based practice activities were set for up to 5-10 mins daily on treatment days and 15 mins twice daily on non-treatment days. Dosage for the NHS speech and language therapy was determined by the local therapist in response to the participants' needs (estimated from prior research that NHS speech and language therapy participants would receive an average of one session per week over six to eight weeks). Local practices for NHS speech and language therapy were accepted, except for those within the LSVT LOUD protocol. Analyses were based on the intention to treat principle. MAIN OUTCOME MEASURES: The primary outcome was total score at three months of self-reported voice handicap index. RESULTS: People who received LSVT LOUD reported lower voice handicap index scores at three months after randomisation than those who did not receive speech and language therapy (-8.0 points (99% confidence interval -13.3 to -2.6); P<0.001). No evidence suggests a difference in voice handicap index scores between NHS speech and language therapy and no speech and language therapy (1.7 points (-3.8 to 7.1); P=0.43). Patients in the LSVT LOUD group also reported lower voice handicap index scores than did those randomised to NHS speech and language therapy (-9.6 points (-14.9 to -4.4); P<0.001). 93 adverse events (predominately vocal strain) were reported in the LSVT LOUD group, 46 in the NHS speech and language therapy group, and none in the no speech and language therapy group. No serious adverse events were recorded. CONCLUSIONS: LSVT LOUD was more effective at reducing the participant reported impact of voice problems than was no speech and language therapy and NHS speech and language therapy. NHS speech and language therapy showed no evidence of benefit compared with no speech and language therapy. TRIAL REGISTRATION: ISRCTN registry ISRCTN12421382.


Assuntos
Disartria , Terapia da Linguagem , Doença de Parkinson , Fonoterapia , Humanos , Doença de Parkinson/complicações , Disartria/etiologia , Disartria/terapia , Disartria/reabilitação , Masculino , Feminino , Fonoterapia/métodos , Idoso , Terapia da Linguagem/métodos , Reino Unido , Pessoa de Meia-Idade , Resultado do Tratamento , Treinamento da Voz , Medicina Estatal
9.
Front Public Health ; 12: 1351808, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38979043

RESUMO

Introduction: Parkinson's disease (PD) is an incurable, progressive, neurodegenerative disorder. As PD advances and symptoms progress, patients become increasingly dependent on family and carers. Traditional cost-effectiveness analyses (CEA) only consider patient and payer-related outcomes, failing to acknowledge impacts on families, carers, and broader society. This novel Social Return on Investment (SROI) analysis aimed to evaluate the broader impact created by improving access to levodopa (LD) device-aided therapies (DATs) for people living with advanced PD (aPD) in Australia. Methods: A forecast SROI analysis over a three-year time horizon was conducted. People living with aPD and their families were recruited for qualitative interviews or a quantitative survey. Secondary research and clinical trial data was used to supplement the primary research. Outcomes were valued and assessed in a SROI value map in Microsoft Excel™. Financial proxies were assigned to each final outcome based on willingness-to-pay, economic valuation, and replacement value. Treatment cost inputs were sourced from Pharmaceutical Benefits Schedule (PBS) and Medicare Benefits Scheme (MBS) published prices. Results: Twenty-four interviews were conducted, and 55 survey responses were received. For every $1 invested in access to LD-based DATs in Australia, an estimated $1.79 of social value is created. Over 3 years, it was estimated $277.16 million will be invested and $406.77 million of social return will be created. This value is shared between people living with aPD (27%), their partners (22%), children (36%), and the Australian Government (15%). Most of the value created is social and emotional in nature, including reduced worry, increased connection to family and friends, and increased hope for the future. Discussion: Investment in LD-based DATs is expected to generate a positive social return. Over 50% of the value is created for the partners and children of people living with aPD. This value would not be captured in traditional CEA. The SROI methodology highlights the importance of investing in aPD treatment, capturing the social value created by improved access to LD-based DATs.


Assuntos
Análise Custo-Benefício , Levodopa , Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/economia , Doença de Parkinson/terapia , Austrália , Levodopa/uso terapêutico , Levodopa/economia , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Inquéritos e Questionários , Antiparkinsonianos/uso terapêutico , Antiparkinsonianos/economia , Pesquisa Qualitativa , Entrevistas como Assunto
10.
Int J Biol Sci ; 20(9): 3302-3316, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38993558

RESUMO

Background: Parkinson's disease (PD) is marked by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to motor and cognitive dysfunctions. The molecular mechanisms underlying synaptic alterations in PD remain elusive, with a focus on the role of Itga5 in synaptic integrity and motor coordination and TAT-Itga5 was designed to suppress PTEN activity in this investigation. Methods: This study utilized MPTP-induced PD animal models to investigate the expression and role of Itga5 in the striatum. Techniques included quantitative PCR, Western blotting, immunostaining, CRISPR-CasRx-mediated knockdown, electrophysiological assays, behavioral tests, and mass spectrometry. Results: Itga5 expression was significantly reduced in MPTP-induced PD models. In these models, a marked decrease in dendritic spine density and a shift towards thinner spines in striatal GABA neurons were observed, suggesting impaired synaptic integration. Knockdown of Itga5 resulted in reduced dendritic branching, decreased mushroom spines, and increased thin spines, altering synaptic architecture. Electrophysiological analyses revealed changes in action potential and spontaneous excitatory postsynaptic currents, indicating altered synaptic transmission. Motor behavior assessments showed that Itga5 deficiency led to impairments in fine motor control and coordination. Furthermore, Itga5 was found to interact with PTEN, affecting AKT signaling crucial for synaptic development and motor coordination. Conclusion: The study demonstrates that Itga5 plays a critical role in maintaining synaptic integrity and motor coordination in PD. The Itga5-PTEN-AKT pathway represents a potential therapeutic target for addressing synaptic and motor dysfunctions in PD.


Assuntos
PTEN Fosfo-Hidrolase , Doença de Parkinson , Transdução de Sinais , Animais , PTEN Fosfo-Hidrolase/metabolismo , PTEN Fosfo-Hidrolase/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/genética , Masculino , Camundongos , Corpo Estriado/metabolismo , Camundongos Endogâmicos C57BL , Integrina alfa5/metabolismo , Integrina alfa5/genética , Sinapses/metabolismo , Modelos Animais de Doenças
11.
Int J Mol Sci ; 25(13)2024 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-39000288

RESUMO

Parkinson's disease (PD) is a gradually worsening neurodegenerative disorder affecting the nervous system, marked by a slow progression and varied symptoms. It is the second most common neurodegenerative disease, affecting over six million people in the world. Its multifactorial etiology includes environmental, genomic, and epigenetic factors. Clinical symptoms consist of non-motor and motor symptoms, with motor symptoms being the classic presentation. Therapeutic approaches encompass pharmacological, non-pharmacological, and surgical interventions. Traditional pharmacological treatment consists of administering drugs (MAOIs, DA, and levodopa), while emerging evidence explores the potential of antidiabetic agents for neuroprotection and gene therapy for attenuating parkinsonian symptoms. Non-pharmacological treatments, such as exercise, a calcium-rich diet, and adequate vitamin D supplementation, aim to slow disease progression and prevent complications. For those patients who have medically induced side effects and/or refractory symptoms, surgery is a therapeutic option. Deep brain stimulation is the primary surgical option, associated with motor symptom improvement. Levodopa/carbidopa intestinal gel infusion through percutaneous endoscopic gastrojejunostomy and a portable infusion pump succeeded in reducing "off" time, where non-motor and motor symptoms occur, and increasing "on" time. This article aims to address the general aspects of PD and to provide a comparative comprehensive review of the conventional and the latest therapeutic advancements and emerging treatments for PD. Nevertheless, further studies are required to optimize treatment and provide suitable alternatives.


Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/terapia , Levodopa/uso terapêutico , Estimulação Encefálica Profunda/métodos , Antiparkinsonianos/uso terapêutico , Terapia Genética/métodos , Animais
12.
Int J Mol Sci ; 25(13)2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-39000460

RESUMO

Aberrant aggregation of misfolded alpha-synuclein (α-syn), a major pathological hallmark of related neurodegenerative diseases such as Parkinson's disease (PD), can translocate between cells. Ubiquitin-like 3 (UBL3) is a membrane-anchored ubiquitin-fold protein and post-translational modifier. UBL3 promotes protein sorting into small extracellular vesicles (sEVs) and thereby mediates intercellular communication. Our recent studies have shown that α-syn interacts with UBL3 and that this interaction is downregulated after silencing microsomal glutathione S-transferase 3 (MGST3). However, how MGST3 regulates the interaction of α-syn and UBL3 remains unclear. In the present study, we further explored this by overexpressing MGST3. In the split Gaussia luciferase complementation assay, we found that the interaction between α-syn and UBL3 was upregulated by MGST3. While Western blot and RT-qPCR analyses showed that silencing or overexpression of MGST3 did not significantly alter the expression of α-syn and UBL3, the immunocytochemical staining analysis indicated that MGST3 increased the co-localization of α-syn and UBL3. We suggested roles for the anti-oxidative stress function of MGST3 and found that the effect of MGST3 overexpression on the interaction between α-syn with UBL3 was significantly rescued under excess oxidative stress and promoted intracellular α-syn to extracellular transport. In conclusion, our results demonstrate that MGST3 upregulates the interaction between α-syn with UBL3 and promotes the interaction to translocate intracellular α-syn to the extracellular. Overall, our findings provide new insights and ideas for promoting the modulation of UBL3 as a therapeutic agent for the treatment of synucleinopathy-associated neurodegenerative diseases.


Assuntos
Glutationa Transferase , Estresse Oxidativo , Ubiquitinas , alfa-Sinucleína , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Humanos , Glutationa Transferase/metabolismo , Glutationa Transferase/genética , Ubiquitinas/metabolismo , Ubiquitinas/genética , Regulação para Cima , Transporte Proteico , Doença de Parkinson/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/patologia , Ligação Proteica
13.
Int J Mol Sci ; 25(13)2024 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-39000550

RESUMO

The effect of the modulators of the mitochondrial ATP-dependent potassium channel (mitoKATP) on the structural and biochemical alterations in the substantia nigra and brain tissues was studied in a rat model of Parkinson's disease induced by rotenone. It was found that, in experimental parkinsonism accompanied by characteristic motor deficits, both neurons and the myelin sheath of nerve fibers in the substantia nigra were affected. Changes in energy and ion exchange in brain mitochondria were also revealed. The nucleoside uridine, which is a source for the synthesis of the mitoKATP channel opener uridine diphosphate, was able to dose-dependently decrease behavioral disorders and prevent the death of animals, which occurred for about 50% of animals in the model. Uridine prevented disturbances in redox, energy, and ion exchanges in brain mitochondria, and eliminated alterations in their structure and the myelin sheath in the substantia nigra. Cytochemical examination showed that uridine restored the indicators of oxidative phosphorylation and glycolysis in peripheral blood lymphocytes. The specific blocker of the mitoKATP channel, 5-hydroxydecanoate, eliminated the positive effects of uridine, suggesting that this channel is involved in neuroprotection. Taken together, these findings indicate the promise of using the natural metabolite uridine as a new drug to prevent and, possibly, stop the progression of Parkinson's disease.


Assuntos
Mitocôndrias , Canais de Potássio , Rotenona , Uridina , Animais , Uridina/farmacologia , Uridina/metabolismo , Ratos , Canais de Potássio/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Masculino , Modelos Animais de Doenças , Doença de Parkinson/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/etiologia , Doença de Parkinson/patologia , Substância Negra/metabolismo , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Fármacos Neuroprotetores/farmacologia , Fosforilação Oxidativa/efeitos dos fármacos , Ratos Wistar , Ácidos Decanoicos/farmacologia , Hidroxiácidos/farmacologia
14.
Sensors (Basel) ; 24(13)2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-39001075

RESUMO

INTRODUCTION: The current approach to assessing bradykinesia in Parkinson's Disease relies on the Unified Parkinson's Disease Rating Scale (UPDRS), which is a numeric scale. Inertial sensors offer the ability to probe subcomponents of bradykinesia: motor speed, amplitude, and rhythm. Thus, we sought to investigate the differential effects of high-frequency compared to low-frequency subthalamic nucleus (STN) deep brain stimulation (DBS) on these quantified facets of bradykinesia. METHODS: We recruited advanced Parkinson's Disease subjects with a chronic bilateral subthalamic nucleus (STN) DBS implantation to a single-blind stimulation trial where each combination of medication state (OFF/ON), electrode contacts, and stimulation frequency (60 Hz/180 Hz) was assessed. The Kinesia One sensor system was used to measure upper limb bradykinesia. For each stimulation trial, subjects performed extremity motor tasks. Sensor data were recorded continuously. We identified STN DBS parameters that were associated with improved upper extremity bradykinesia symptoms using a mixed linear regression model. RESULTS: We recruited 22 subjects (6 females) for this study. The 180 Hz STN DBS (compared to the 60 Hz STN DBS) and dopaminergic medications improved all subcomponents of upper extremity bradykinesia (motor speed, amplitude, and rhythm). For the motor rhythm subcomponent of bradykinesia, ventral contacts yielded improved symptom improvement compared to dorsal contacts. CONCLUSION: The differential impact of high- and low-frequency STN DBS on the symptoms of bradykinesia may advise programming for these patients but warrants further investigation. Wearable sensors represent a valuable addition to the armamentarium that furthers our ability to conduct objective, quantitative clinical assessments.


Assuntos
Estimulação Encefálica Profunda , Hipocinesia , Doença de Parkinson , Núcleo Subtalâmico , Humanos , Doença de Parkinson/terapia , Doença de Parkinson/fisiopatologia , Estimulação Encefálica Profunda/métodos , Estimulação Encefálica Profunda/instrumentação , Hipocinesia/terapia , Hipocinesia/fisiopatologia , Núcleo Subtalâmico/fisiopatologia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso
15.
Chem Res Toxicol ; 37(7): 1071-1085, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38958636

RESUMO

Parkinson's disease (PD) affects more people worldwide than just aging alone can explain. This is likely due to environmental influences, genetic makeup, and changes in daily habits. The disease develops in a complex way, with movement problems caused by Lewy bodies and the loss of dopamine-producing neurons. Some research suggests Lewy bodies might start in the gut, hinting at a connection between these structures and gut health in PD patients. These patients often have different gut bacteria and metabolites. Pesticides are known to increase the risk of PD, with evidence showing they harm more than just dopamine neurons. Long-term exposure to pesticides in food might affect the gut barrier, gut bacteria, and the blood-brain barrier, but the exact link is still unknown. This review looks at how pesticides and gut bacteria separately influence PD development and progression, highlighting the harmful effects of pesticides and changes in gut bacteria. We have examined the interaction between pesticides and gut bacteria in PD patients, summarizing how pesticides cause imbalances in gut bacteria, the resulting changes, and their overall effects on the PD prognosis.


Assuntos
Microbioma Gastrointestinal , Doença de Parkinson , Praguicidas , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Praguicidas/metabolismo , Doença de Parkinson/microbiologia , Doença de Parkinson/metabolismo , Animais
16.
Acta Neuropathol ; 148(1): 4, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38995454

RESUMO

Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by neuronal loss and gliosis, with oligodendroglial cytoplasmic inclusions (GCIs) containing α-synuclein being the primary pathological hallmark. Clinical presentations of MSA overlap with other parkinsonian disorders, such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and progressive supranuclear palsy (PSP), posing challenges in early diagnosis. Numerous studies have reported alterations in DNA methylation in neurodegenerative diseases, with candidate loci being identified in various parkinsonian disorders including MSA, PD, and PSP. Although MSA and PSP present with substantial white matter pathology, alterations in white matter have also been reported in PD. However, studies comparing the DNA methylation architectures of white matter in these diseases are lacking. We therefore aimed to investigate genome-wide DNA methylation patterns in the frontal lobe white matter of individuals with MSA (n = 17), PD (n = 17), and PSP (n = 16) along with controls (n = 15) using the Illumina EPIC array, to identify shared and disease-specific DNA methylation alterations. Genome-wide DNA methylation profiling of frontal lobe white matter in the three parkinsonian disorders revealed substantial commonalities in DNA methylation alterations in MSA, PD, and PSP. We further used weighted gene correlation network analysis to identify disease-associated co-methylation signatures and identified dysregulation in processes relating to Wnt signaling, signal transduction, endoplasmic reticulum stress, mitochondrial processes, RNA interference, and endosomal transport to be shared between these parkinsonian disorders. Our overall analysis points toward more similarities in DNA methylation patterns between MSA and PD, both synucleinopathies, compared to that between MSA and PD with PSP, which is a tauopathy. Our results also highlight several shared DNA methylation changes and pathways indicative of converging molecular mechanisms in the white matter contributing toward neurodegeneration in all three parkinsonian disorders.


Assuntos
Metilação de DNA , Lobo Frontal , Atrofia de Múltiplos Sistemas , Doença de Parkinson , Paralisia Supranuclear Progressiva , Substância Branca , Humanos , Paralisia Supranuclear Progressiva/genética , Paralisia Supranuclear Progressiva/patologia , Metilação de DNA/genética , Atrofia de Múltiplos Sistemas/genética , Atrofia de Múltiplos Sistemas/patologia , Substância Branca/patologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , Idoso , Feminino , Masculino , Lobo Frontal/patologia , Lobo Frontal/metabolismo , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais
17.
Sci Rep ; 14(1): 16091, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38997273

RESUMO

Accumulation of α-synuclein (α-Syn) has been implicated in proteasome and autophagy dysfunction in Parkinson's disease (PD). High frequency electrical stimulation (HFS) mimicking clinical parameters used for deep brain stimulation (DBS) in vitro or DBS in vivo in preclinical models of PD have been found to reduce levels of α-Syn and, in certain cases, provide possible neuroprotection. However, the mechanisms by which this reduction in α-Syn improves cellular dysfunction associated with α-Syn accumulation remains elusive. Using HFS parameters that recapitulate DBS in vitro, we found that HFS led to a reduction of mutant α-Syn and thereby limited proteasome and autophagy impairments due to α-Syn. Additionally, we observed that HFS modulates via the ATP6V0C subunit of V-ATPase and mitigates α-Syn mediated autophagic dysfunction. This study highlights a role for autophagy in reduction of α-Syn due to HFS which may prove to be a viable approach to decrease pathological protein accumulation in neurodegeneration.


Assuntos
Autofagia , alfa-Sinucleína , alfa-Sinucleína/metabolismo , Humanos , Doença de Parkinson/metabolismo , Doença de Parkinson/terapia , Animais , Estimulação Elétrica/métodos , Estimulação Encefálica Profunda/métodos , Complexo de Endopeptidases do Proteassoma/metabolismo , ATPases Vacuolares Próton-Translocadoras/metabolismo , Camundongos
18.
Sci Rep ; 14(1): 16089, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38997314

RESUMO

Retinal hyperspectral imaging (HSI) is a non-invasive in vivo approach that has shown promise in Alzheimer's disease. Parkinson's disease is another neurodegenerative disease where brain pathobiology such as alpha-synuclein and iron overaccumulation have been implicated in the retina. However, it remains unknown whether HSI is altered in in vivo models of Parkinson's disease, whether it differs from healthy aging, and the mechanisms which drive these changes. To address this, we conducted HSI in two mouse models of Parkinson's disease across different ages; an alpha-synuclein overaccumulation model (hA53T transgenic line M83, A53T) and an iron deposition model (Tau knock out, TauKO). In comparison to wild-type littermates the A53T and TauKO mice both demonstrated increased reflectivity at short wavelengths ~ 450 to 600 nm. In contrast, healthy aging in three background strains exhibited the opposite effect, a decreased reflectance in the short wavelength spectrum. We also demonstrate that the Parkinson's hyperspectral signature is similar to that from an Alzheimer's disease model, 5xFAD mice. Multivariate analyses of HSI were significant when plotted against age. Moreover, when alpha-synuclein, iron or retinal nerve fibre layer thickness were added as a cofactor this improved the R2 values of the correlations in certain groups. This study demonstrates an in vivo hyperspectral signature in Parkinson's disease that is consistent in two mouse models and is distinct from healthy aging. There is also a suggestion that factors including retinal deposition of alpha-synuclein and iron may play a role in driving the Parkinson's disease hyperspectral profile and retinal nerve fibre layer thickness in advanced aging. These findings suggest that HSI may be a promising translation tool in Parkinson's disease.


Assuntos
Modelos Animais de Doenças , Envelhecimento Saudável , Imageamento Hiperespectral , Camundongos Transgênicos , Doença de Parkinson , Retina , alfa-Sinucleína , Animais , Doença de Parkinson/metabolismo , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/patologia , Doença de Parkinson/genética , Retina/metabolismo , Retina/diagnóstico por imagem , Retina/patologia , Camundongos , Envelhecimento Saudável/metabolismo , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Imageamento Hiperespectral/métodos , Ferro/metabolismo , Humanos , Masculino , Camundongos Knockout
19.
Nutrients ; 16(13)2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38999791

RESUMO

With the recognition of the importance of the gut-brain axis in Parkinson's disease (PD) etiology, there is increased interest in developing therapeutic strategies that target α-synuclein, the hallmark abhorrent protein of PD pathogenesis, which may originate in the gut. Research has demonstrated that inhibiting the aggregation, oligomerization, and fibrillation of α-synuclein are key strategies for disease modification. Polyphenols, which are rich in fruits and vegetables, are drawing attention for their potential role in this context. In this paper, we reviewed how polyphenols influence the composition and functional capabilities of the gut microbiota and how the resulting microbial metabolites of polyphenols may potentially enhance the modulation of α-synuclein aggregation. Understanding the interaction between polyphenols and gut microbiota and identifying which specific microbes may enhance the efficacy of polyphenols is crucial for developing therapeutic strategies and precision nutrition based on the microbiome.


Assuntos
Eixo Encéfalo-Intestino , Microbioma Gastrointestinal , Doença de Parkinson , Polifenóis , alfa-Sinucleína , Doença de Parkinson/metabolismo , Doença de Parkinson/microbiologia , Doença de Parkinson/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Polifenóis/farmacologia , Humanos , alfa-Sinucleína/metabolismo , Eixo Encéfalo-Intestino/fisiologia , Animais , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos
20.
Nutrients ; 16(13)2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38999824

RESUMO

Parkinson's disease (PD) is a degenerative neurological disorder defined by the deterioration and loss of dopamine-producing neurons in the substantia nigra, leading to a range of motor impairments and non-motor symptoms. The underlying mechanism of this neurodegeneration remains unclear. This research examined the neuroprotective properties of Ecklonia cava polyphenols (ECPs) in mitigating neuronal damage induced by rotenone via the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway. Using human neuroblastoma SH-SY5Y cells and PD model mice, we found that ECP, rich in the antioxidant polyphenol phlorotannin, boosted the gene expression and functionality of the antioxidant enzyme NAD(P)H quinone oxidoreductase-1. ECP also promoted Nrf2 nuclear translocation and increased p62 expression, suggesting that p62 helps sustain Nrf2 activation via a positive feedback loop. The neuroprotective effect of ECP was significantly reduced by Compound C (CC), an AMP-activated protein kinase (AMPK) inhibitor, which also suppressed Nrf2 nuclear translocation. In PD model mice, ECPs improved motor functions impaired by rotenone, as assessed by the pole test and wire-hanging test, and restored intestinal motor function and colon tissue morphology. Additionally, ECPs increased tyrosine hydroxylase expression in the substantia nigra, indicating a protective effect on dopaminergic neurons. These findings suggest that ECP has a preventative effect on PD.


Assuntos
Fator 2 Relacionado a NF-E2 , Fármacos Neuroprotetores , Doença de Parkinson , Polifenóis , Rotenona , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Polifenóis/farmacologia , Humanos , Fármacos Neuroprotetores/farmacologia , Camundongos , Masculino , Doença de Parkinson/metabolismo , Doença de Parkinson/prevenção & controle , Doença de Parkinson/tratamento farmacológico , Elementos de Resposta Antioxidante/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Modelos Animais de Doenças , Linhagem Celular Tumoral , Antioxidantes/farmacologia , Camundongos Endogâmicos C57BL , Extratos Vegetais/farmacologia , NAD(P)H Desidrogenase (Quinona)/metabolismo
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