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Induced pluripotent stem cell-related approaches to generate dopaminergic neurons for Parkinson's disease

Neural Regeneration research 2025年第11期20卷 3193-3206页

作者： Ling-Xiao Yi Hui Ren Woon Genevieve Saw Li Zeng Eng King Tan Zhi Dong Zhou National Neuroscience Institute Singapore Nanyang Technology University Singapore Department of Neurology Singapore General HospitalSingapore Signature Research Program in Neuroscience and Behavioral Disorders Duke-NUS Medical SchoolSingapore

The progressive loss of dopaminergic neurons in affected patient brains is one of the pathological features of Parkinson's disease,the second most common human neurodegenerative *** the detailed pathogenesis accounting for dopaminergic neuron degeneration in Parkinson's disease is still unclear,the advancement of stem cell approaches has shown promise for Parkinson's disease research and *** induced pluripotent stem cells have been commonly used to generate dopaminergic neurons,which has provided valuable insights to improve our understanding of Parkinson's disease pathogenesis and contributed to anti-Parkinson's disease *** current review discusses the practical approaches and potential applications of induced pluripotent stem cell techniques for generating and differentiating dopaminergic neurons from induced pluripotent stem *** benefits of induced pluripotent stem cell-based research are *** dopaminergic neuron differentiation protocols from induced pluripotent stem cells are *** emerging three-dimension-based brain organoid models compared with conventional two-dimensional cell culture are ***,limitations,challenges,and future directions of induced pluripotent stem cell–based approaches are analyzed and proposed,which will be significant to the future application of induced pluripotent stem cell-related techniques for Parkinson's disease.

关键词： dopaminergic neurons induced pluripotent stem cells Parkinson's disease stem cell approaches

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Glucagon-like peptide-1 receptor agonists in neurodegenerative diseases: Promises and challenges

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Pharmacological research 2025年 216卷 107770页

作者： Zhou, Zhi Dong Yi, Lingxiao Popławska-Domaszewicz, Karolina Chaudhuri, Kallol Ray Jankovic, Joseph Tan, Eng King National Neuroscience Institute of Singapore 11 Jalan Tan Tock Seng 308433 Singapore Signature Research Program in Neuroscience and Behavioral Disorders Duke-NUS Medical School 8 College Road 169857 Singapore Department of Neurology Poznan University of Medical Sciences Poznan 60-355 Poland Parkinson's Foundation Centre of Excellence King's College Hospital Denmark Hill London SE5 9RS United Kingdom Department of Basic and Clinical Neuroscience The Maurice Wohl Clinical Neuroscience Institute King's College London Cutcombe Road London SE5 9RT United Kingdom Parkinson's Disease Center and Movement Disorders Clinic Department of Neurology Baylor College of Medicine Houston TX United States

Glucagon-like peptide-1 (GLP-1) receptor agonists (GRA) belong to a class of compounds that reduce blood glucose and energy intake by simulating actions of endogenous incretin hormone GLP-1 after it is released by the gut following food consumption. They are used to treat type 2 diabetes mellitus (T2DM) and obesity and have systemic effects on various organs, including the brain, liver, pancreas, heart, and the gut. Patients with T2DM have a higher risk of developing neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), accompanied by more severe motor deficits and faster disease progression, suggesting dysregulation of insulin signaling in these diseases. Experimental studies have shown that GRA have protective effects to modulate neuroinflammation, oxidative stress, mitochondrial and autophagic functions, and protein misfolding. Hence the compounds have generated enormous interest as novel therapeutic agents against NDs. To date, clinical trials have shown that three GRA, exenatide, liraglutide and lixisenatide can improve motor deficits as an add-on therapy in PD patients and liraglutide can improve cognitive function in AD patients. The neuroprotective effects of these and other GRA, such as PT320 (a sustained-released exenatide) and semaglutide, are still under investigation. The dual GLP-1/gastric inhibitory polypeptide (GIP) receptor agonists have been demonstrated to have beneficial effects in AD and PD mice models. Overall, GRA are highly promising novel drugs, but future clinical studies should identify which subsets of patients should be targeted as potential candidates for their symptomatic and/or neuroprotective benefits, investigate whether combinations with other classes of drugs can further augment their efficacy, and evaluate their long-term disease-modifying and adverse effects. © 2025 The Authors

关键词： Alzheimer's disease GLP-1 receptor agonists Glucagon-like peptide-1 Neurodegenerative diseases Parkinsons' disease Type 2 diabetes mellitus

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Molecular targets for modulating the protein translation vital to proteostasis and neuron degeneration in Parkinson’s disease

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Translational Neurodegeneration 2019年第1期8卷 63-76页

作者： Zhi Dong Zhou Thevapriya Selvaratnam Ji Chao Tristan Lee Yin Xia Chao Eng-King Tan Department of Research National Neuroscience Institute11 Jalan Tan Tock SengSingapore 308433Singapore Department of Neurology Singapore General HospitalOutram RoadSingapore 169608Singapore Signature Research Program in Neuroscience and Behavioural Disorders Duke-NUS Medical School Singapore8 College RoadSingaporeSingapore

Parkinson’s disease(PD)is the most common neurodegenerative movement disorder,which is characterized by the progressive loss of dopaminergic neurons in the Substantia Nigra pars compacta concomitant with Lewy body formation in affected brain *** detailed pathogenic mechanisms underlying the selective loss of dopaminergic neurons in PD are unclear,and no drugs or treatments have been developed to alleviate progressive dopaminergic neuron degeneration in ***,the formation ofα-synuclein-positive protein aggregates in Lewy body has been identified as a common pathological feature of PD,possibly stemming from the consequence of protein misfolding and dysfunctional *** is the mechanism for maintaining protein homeostasis via modulation of protein translation,enhancement of chaperone capacity and the prompt clearance of misfolded protein by the ubiquitin proteasome system and *** protein translation and impaired capacities of chaperone or protein degradation can disturb proteostasis processes,leading to pathological protein aggregation and neurodegeneration in *** recent years,multiple molecular targets in the modulation of protein translation vital to proteostasis and dopaminergic neuron degeneration have been *** potential pathophysiological and therapeutic significance of these molecular targets to neurodegeneration in PD is highlighted.

关键词： Molecular targets Neuron degeneration Parkinson’s disease Protein aggregation Protein translation Proteostasis

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Role of dopamine in the pathophysiology of Parkinson’s disease

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Translational Neurodegeneration 2023年第1期12卷 281-295页

作者： Zhi Dong Zhou Ling Xiao Yi Dennis Qing Wang Tit Meng Lim Eng King Tan National Neuroscience Institute of Singapore 11 Jalan Tan Tock SengSingapore 308433Singapore Department of Neurology Singapore General HospitalOutram RoadSingapore 169608Singapore Signature Research Program in Neuroscience and Behavioral Disorders Duke-NUS Graduate Medical School Singapore8 College RoadSingapore 169857Singapore Department of Neurology Zhujiang HospitalSouthern Medical UniversityGuangzhou 510280China Department of Biological Science National University of SingaporeSingapore 119077Singapore

A pathological feature of Parkinson’s disease(PD)is the progressive loss of dopaminergic neurons and decreased dopamine(DA)content in the substantia nigra pars compacta in PD *** is the neurotransmitter of dopaminergic *** evidence suggests that DA interacts with environmental and genetic factors to contribute to PD *** of DA synthesis,storage,transportation and metabolism have been shown to promote neurodegeneration of dopaminergic neurons in various PD *** is unstable and can undergo oxidation and metabolism to produce multiple reactive and toxic by-products,including reactive oxygen species,DA quinones,and 3,*** we summarize and highlight recent discoveries on DA-linked pathophysiologic pathways,and discuss the potential protective and therapeutic strategies to mitigate the complications associated with DA.

关键词： Dopamine Dopamine quinones 3,4-Dihydroxyphenylacetaldehyde Neurodegeneration Pathogenesis Parkinson’s disease Reactive oxygen species Therapeutic strategies

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Intestine-derived α-synuclein initiates and aggravates pathogenesis of Parkinson’s disease in Drosophila

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Translational Neurodegeneration 2022年第1期11卷 262-279页

作者： Wei Liu Kah-Leong Lim Eng-King Tan School of Plant Protection Anhui Province Key Laboratory of Crop Integrated Pest ManagementAnhui Province Engineering Laboratory for Green Pesticide Development and ApplicationAnhui Agricultural UniversityHefei 230036China Department of Neurology National Neuroscience InstituteSingapore 308433Singapore Department of Research National Neuroscience InstituteSingaporeSingapore Research Lee Kong Chian School of Medi-cineSingaporeSingapore Neuroscience and Behavioural Disorders Program Duke-NUS Medical SchoolSingapore 169857Singapore.

Background:Aberrant aggregation ofα-synuclein(α-syn)is a key pathological feature of Parkinson’s disease(PD),but the precise role of intestinalα-syn in the progression of PD is *** a number of genetic Drosophila models of PD,α-syn was frequently ectopically expressed in the neural system to investigate the ***:We investigated the potential role of intestinalα-syn in PD pathogenesis using a Drosophila ***α-syn was overexpressed in Drosophila guts,and life span,survival,immunofluorescence and climbing were ***,Western blotting and reactive oxygen species(ROS)staining were performed to assess the effects of intestinalα-syn on intestinal ***‐throughput RNA and 16S rRNA gene sequencing,quantitative RT‐PCR,immunofluorescence,and ROS staining were performed to determine the underlying molecular ***:We found that the intestinalα-syn alone recapitulated many phenotypic and pathological features of PD,including impaired life span,loss of dopaminergic neurons,and progressive motor *** intestine-derivedα-syn disrupted intestinal homeostasis and accelerated the onset of intestinal ***,intestinal expression ofα-syn induced dysbiosis,while microbiome depletion was efficient to restore intestinal homeostasis and ameliorate the progression of ***α-syn triggered ROS,and eventually led to the activation of the dual oxidase(DUOX)-ROS-Jun N-terminal Kinase(JNK)*** addition,α-syn from both the gut and the brain synergized to accelerate the progression of ***:The intestinal expression ofα-syn recapitulates many phenotypic and pathologic features of PD,and induces dysbiosis that aggravates the pathology through the DUOX-ROS-JNK pathway in *** findings provide new insights into the role of intestinalα-syn in PD pathophysiology.

关键词： Intestine α-Synuclein Parkinson’s disease Microbiome

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Erratum to: Mitochondrial CHCHD-Containing Proteins: Physiologic Functions and Link with Neurodegenerative Diseases

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Molecular neurobiology 2017年第7期54卷 5547-5549页

作者： Zhi-Dong Zhou Wuan-Ting Saw Eng-King Tan National Neuroscience Institute of Singapore 11 Jalan Tan Tock Seng Singapore 308433 Singapore. Zhidong_zhou@nni.com.sg. Signature Research Program in Neuroscience and Behavioural Disorders Duke-NUS Graduate Medical School Singapore 8 College Road Singapore 169857 Singapore. Zhidong_zhou@nni.com.sg. National Neuroscience Institute of Singapore 11 Jalan Tan Tock Seng Singapore 308433 Singapore. National Neuroscience Institute of Singapore 11 Jalan Tan Tock Seng Singapore 308433 Singapore. Tan.eng.king@sgh.com.sg. Signature Research Program in Neuroscience and Behavioural Disorders Duke-NUS Graduate Medical School Singapore 8 College Road Singapore 169857 Singapore. Tan.eng.king@sgh.com.sg. Department of Neurology Singapore General Hospital Outram Road Singapore 169608 Singapore. Tan.eng.king@sgh.com.sg.

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A pragmatic pilot randomized trial to investigate the effectiveness of behavioural activation group therapy in reducing depressive symptoms and improving quality of life in patients with depression: The BRAVE pilot trial protocol

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Pilot and Feasibility Studies 2015年第1期1卷 1-13页

作者： Samaan, Zainab Litke, Kathryn McCabe, Kathleen Dennis, Brittany Whattam, Jeff Garrick, Laura Tabak, Terri Ann Simons, Scott Chalmers, Sandra Key, Brenda Vanstone, Meredith Xie, Feng Guyatt, Gordon Thabane, Lehana McMaster University Department of Psychiatry Behavioural Neuroscience Hamilton ON Canada St. Joseph's Healthcare Hamilton Mood Disorders Research Unit Hamilton ON Canada McMaster University Department of Clinical Epidemiology and Biostatistics Hamilton ON Canada McMaster University Population Genomics Program Chanchlani Research Centre Hamilton ON Canada McMaster University Department of Medicine Hamilton ON Canada Centre for Evaluation of Medicine Hamilton ON Canada System-Linked Research Unit Hamilton ON Canada McMaster University Department of Anaesthesia Hamilton ON Canada McMaster University Department of Paediatrics Hamilton ON Canada

Background: Depression is a common disorder with a lifetime prevalence of 16 %. Despite the availability of several treatment options for depression, many patients do not respond to treatment and develop chronic illness associated with several secondary comorbidities. behavioural activation (BA) is a simple therapy that has the potential for improving symptoms of depression and quality of life in patients with depression. The effectiveness of BA has not, however, been tested in a group format for patients with moderate to severe depression attending a specialized mood disorders tertiary care setting. Group format has the advantage of treating more patients at the same time especially in resource-limited settings. The primary objective of this pilot study is to test the feasibility of a main trial by assessing the recruitment and retention rates, average group size, completion of data and resources needed and receive the participants' feedback on the intervention. The secondary objective is to explore the change in mood and quality of life measures in adults with depression receiving BA. Methods/Design: Using a pragmatic pilot randomized controlled trial design, we will test the feasibility of a large trial to assess the effectiveness of BA added to usual care compared to a depression support group with usual care. Participants will be randomized after obtaining informed written consent to one of two study arms. Face-to-face group therapy will be provided in a hospital setting by trained therapists. Intervention and control groups will be seen twice weekly for 10 weeks and then once weekly for further 8 weeks. Participants will be completing mood symptom scales, quality of life questionnaires and anthropometric measures and provide blood samples for future analysis of biomarkers of response to treatment. During the pilot study we will also solicit participants' feedback and experience regarding the number, frequency and contents of the sessions as well as to explore

关键词： Activation Adult behavioural Depression Group Pilot Pragmatic Protocol Randomized Trial

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Symptom network connectivity indices as predictors of relapse in major depressive disorder

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Psychiatry research 2025年 350卷

作者： Abraham Nunes Barbara Pavlova John-Jose Nuñez Lena C. Quilty Jane A. Foster Kate L. Harkness Keith Ho Raymond W. Lam Qingqin S. Li Roumen Milev Susan Rotzinger Claudio N. Soares Valerie H. Taylor Gustavo Turecki Sidney H. Kennedy Benicio N. Frey Frank Rudzicz Rudolf Uher Department of Psychiatry Dalhousie University Halifax Nova Scotia Canada Faculty of Computer Science Dalhousie University Halifax Nova Scotia Canada Mood Disorders Program Nova Scotia Health Authority Halifax NS Canada Department of Psychiatry University of British Columbia Vancouver British Columbia Canada Campbell Family Mental Health Research Institute CAMH Toronto ON Canada Department of Psychiatry & Behavioural Neurosciences McMaster University Hamilton ON Canada Department of Psychiatry UT Southwestern Medical Center Dallas TX USA Department of Psychology Queen’s University Kingston Ontario Canada Mood Disorders Program and Women’s Health Concerns Clinic St. Joseph’s Healthcare Hamilton ON Canada Neuroscience Janssen Research & Development LLC Titusville NJ USA Department of Psychiatry Providence Care Queen's University Kingston ON Canada Cumming School of Medicine Department of Psychiatry University of Calgary Calgary AB Canada Douglas Institute Department of Psychiatry McGill University Montreal QC Canada Department of Psychiatry University of Toronto Toronto ON Canada Vector Institute for Artificial Intelligence Toronto Ontario Canada

Major Depressive Disorder (MDD) demonstrates heterogeneous symptom profiles and a high relapse risk. Understanding how symptom interactions relate to relapse in MDD may enhance maintenance strategies. We thus investigated how connectivity in depressive symptom networks relates to relapse in MDD. We analyzed longitudinal data from 87 patients with remitted MDD who were followed for an average of 12 months. Patient-level symptom networks were estimated using multilevel graphical vector autoregression applied to weekly self-ratings of the Quick Inventory of Depressive Symptomatology. We calculated patient-specific network connectivity indices, including symptom network density (SND), vertex cover (VC) size, and minimal dominating set (MDS) size. Cox proportional hazards models assessed associations between these indices and time to relapse, controlling for baseline symptom severity. Higher SND and larger VC size were significantly associated with an increased relapse risk (HR for SND = 2.03, 95 % CI [1.44, 2.87], p < 0.001; HR for VC = 2.77, 95 % CI [1.79, 4.30], p < 0.001). Conversely, a larger MDS size was associated with a lower risk of relapse (HR 0.47, 95 % CI [0.31, 0.70], p < 0.001). Exploratory analyses showed that the strength centrality of sadness, difficulty concentrating, pessimism, suicidality, and low interest portend a higher relapse risk. Hyperconnectivity among depressive symptom networks may indicate vulnerability to relapse in MDD. Our results further support the potential utility of symptom network-based analyses for predicting outcomes in MDD. Future studies should evaluate whether symptom network-based analyses can provide markers for personalized treatment planning.

关键词： Major depressive disorder Relapse Survival analysis Network analysis

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Depth-targeted intracortical microstroke by two-photon photothrombosis in rodent brain

Depth-targeted intracortical microstroke by two-photon photo...

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Clinical and Translational Biophotonics, Translational 2022

作者： Fukuda, Masahiro Matsumura, Takayoshi Suda, Toshio Hirase, Hajime International Research Center for Medical Sciences Kumamoto University 2-2-1 Honjo Chuo-ku Kumamoto860-0811 Japan Signature Program in Neuroscience and Behavioral Disorders Duke-NUS Medical School 8 college Road Singapore169857 Singapore Division of Inflammation Research Center for Molecular Medicine Jichi Medical University 3311-1 Yakushiji Tochigi Shimotsuke329-0498 Japan Cancer Science Institute of Singapore National University of Singapore 14 Medical Drive #12-01 Singapore117599 Singapore Center for Translational Neuromedicine Faculty of Health and Life Sciences University of Copenhagen Blegdamsvej 3B Copenhagen N2200 Denmark

We have developed depth-targeted Photothrombosis (DTPT) technique that can target a single vessel in the cortical parenchyma by two-photon excitation. Rose Bengal-mediated DTPT could be induced at 720 nm scanning with... 详细信息

ISBN: (纸本)9781557528209

关键词： Photons

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Psychotic-Like Symptoms and the Temporal Lobe in Trauma-Related disorders: Diagnosis, Treatment, and Assessment of Potential Malingering

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Chronic Stress 2018年 2卷

作者： Schiavone, Francesca L. McKinnon, Margaret C. Lanius, Ruth A. Department of Psychiatry University of Toronto Toronto ON Canada Mood Disorders Program St. Joseph’s Healthcare Hamilton ON Canada Department of Psychiatry and Behavioural Neuroscience McMaster University Hamilton ON Canada Homewood Research Institute Guelph ON Canada Department of Psychiatry University of Western Ontario London ON Canada Department of Neuroscience University of Western Ontario London ON Canada

Objective: To overview the phenomenology, etiology, assessment, and treatment of psychotic-like symptoms in trauma-related disorders focusing on the proposed role of temporal lobe dysfunction. Method: We describe the literature pertaining to (i) psychotic-like symptoms and temporal lobe dysfunction in trauma-related disorders and (ii) psychological testing profiles in trauma-related disorders. We define trauma-related disorders as borderline personality disorder, post-traumatic stress disorder, and the dissociative disorders. Our search terms were dissociative disorders, temporal lobe, trauma, post-traumatic stress disorder, borderline personality disorder, psychosis, and malingering. Results: Trauma-related psychotic-like symptoms are common and can differ in phenomenology from primary psychotic symptoms. Hallucinations consist of auditory and nonauditory content that may or may not relate to traumatic content. Child voices are highly suggestive of complex dissociative disorders. Critically, not only do these symptoms resemble those seen in temporal lobe epilepsy, but the temporal lobe is implicated in trauma-related disorders, thus providing a plausible neurobiological explanation. Despite such evidence, these symptoms are frequently considered atypical and misdiagnosed. Indeed, common structured psychological assessment tools categorize these symptoms as possible indicators of invalid testing profiles. Conclusion: Psychotic-like symptoms are common in trauma-related disorders, may be related to temporal lobe dysfunction, and are frequently misinterpreted. This may lead to ineffective treatment and inappropriate determinations of malingering in the forensic system. © The Author(s) 2018.

关键词： dissociative disorders malingering psychological trauma psychosis temporal lobe epilepsy

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