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neurodegenerative diseases:a hotbed for splicing defects and the potential therapies

Translational Neurodegeneration 2021年第2期10卷 195-212页

作者： Dunhui Li Craig Stewart McIntosh Frank Louis Mastaglia Steve Donald Wilton May Thandar Aung-Htut Centre for Molecular Medicine and Innovative Therapeutics Health Futures InstituteMurdoch UniversityPerthWestern AustraliaAustralia Perron Institute for Neurological and Translational Science Centre for Neuromuscular and Neurological DisordersThe University of Western AustraliaPerthWestern AustraliaAustralia

Precursor messenger RNA(pre-mRNA)splicing is a fundamental step in eukaryotic gene expression that systematically removes non-coding regions(introns)and ligates coding regions(exons)into a continuous message(mature mRNA).This process is highly regulated and can be highly flexible through a process known as alternative splicing,which allows for several transcripts to arise from a single gene,thereby greatly increasing genetic plasticity and the diversity of proteome.Alternative splicing is particularly prevalent in neuronal cells,where the splicing patterns are continuously changing to maintain cellular homeostasis and promote neurogenesis,migration and synaptic function.The continuous changes in splicing patterns and a high demand on many cis-and trans-splicing factors contribute to the susceptibility of neuronal tissues to splicing defects.The resultant neurodegenerative diseases are a large group of disorders defined by a gradual loss of neurons and a progressive impairment in neuronal function.Several of the most common neurodegenerative diseases involve some form of splicing defect(s),such as Alzheimer’s disease,Parkinson’s disease and spinal muscular atrophy.Our growing understanding of RNA splicing has led to the explosion of research in the field of splice-switching antisense oligonucleotide therapeutics.Here we review our current understanding of the effects alternative splicing has on neuronal differentiation,neuronal migration,synaptic maturation and regulation,as well as the impact on neurodegenerative diseases.We will also review the current landscape of splice-switching antisense oligonucleotides as a therapeutic strategy for a number of common neurodegenerative disorders.

关键词： neurodegenerative diseases Parkinson’s disease Alzheimer’s disease Alternative splicing Splicing defects Antisense oligonucleotides Splice-switching Disease-modifying treatment

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Enhancement of lysosome biogenesis as a potential therapeutic approach for neurodegenerative diseases

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Neural Regeneration Research 2023年第11期18卷 2370-2376页

作者： Wenlong Xue Jie Zhang Yang Li Department of Pharmacology State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain ScienceKey Laboratory of Metabolism and Molecular MedicineMinistry of EducationSchool of Basic Medical ScienceFudan UniversityShanghaiChina

Millions of people are suffering from Alzheimer’s disease globally,but there is still no effective treatment for this neurodegenerative disease.Thus,novel therapeutic approaches for Alzheimer’s disease are needed,which requires further evaluation of the regulato ry mechanisms of protein aggregate degradation.Lysosomes are crucial degradative organelles that maintain cellular homeostasis.Transcription factor EB-mediated lysosome biogenesis enhances autolysosomedependent degradation,which subsequently alleviates neurodege nerative diseases,including Alzheimer’s disease,Parkinson’s disease,and Huntington’s disease.In this review,we start by describing the key features of lysosomes,including their roles in nutrient sensing and degradation,and their functional impairments in different neurodegenerative diseases.We also explain the mechanisms—especially the post-translational modifications—which impact transcription factor EB and regulate lysosome biogenesis.Next,we discuss strategies for promoting the degradation of toxic protein aggregates.We describe Proteolysis-Ta rgeting Chimera and related technologies for the targeted degradation of specific proteins.We also introduce a group of LYsosome-Enhancing Compounds,which promote transcription factor EB-mediated lysosome biogenesis and improve learning,memory,and cognitive function in APP-PSEN1 mice.In summary,this review highlights the key aspects of lysosome biology,the mechanisms of transcription factor EB activation and lysosome biogenesis,and the promising strategies which are emerging to alleviate the pathogenesis of neurodegenerative diseases.

关键词： Alzheimer’s disease degradation lysosome biogenesis LYsosome-Enhancing Compounds neurodegenerative diseases post-translational modifications protein aggregates transcription factor EB

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Polymeric nanocarriers for nose-to-brain drug delivery in neurodegenerative diseases and neurodevelopmental disorders

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Acta Pharmaceutica Sinica B 2023年第5期13卷 1866-1886页

作者： Rania Awad Avi Avital Alejandro Sosnik Laboratory of Pharmaceutical Nanomaterials Science Department of Materials Science and EngineeringTechnion-Israel Institute of TechnologyHaifa 3200003Israel Behavioral Neurobiology Laboratory Department of Occupational TherapyFaculty of Social Welfare and Health SciencesUniversity of HaifaHaifa 3498838Israel

neurodegenerative diseases are progressive conditions that affect the neurons of the central nervous system(CNS)and result in their damage and death.Neurodevelopmental disorders include intellectual disability,autism spectrum disorder,and attention-deficit/hyperactivity disorder and stem from the disruption of essential neurodevelopmental processes.The treatment of neurodegenerative and neurodevelopmental conditions,together affecting~120 million people worldwide,is challenged by the blood—brain barrier(BBB)and the blood—cerebrospinal fluid barrier that prevent the crossing of drugs from the systemic circulation into the CNS.The nose-to-brain pathway that bypasses the BBB and increases the brain bioavailability of intranasally administered drugs is promising to improve the treatment of CNS conditions.This pathway is more efficient for nanoparticles than for solutions,hence,the research on intranasal nano-drug delivery systems has grown exponentially over the last decade.Polymeric nanoparticles have become key players in the field owing to the high design and synthetic flexibility.This review describes the challenges faced for the treatment of neurodegenerative and neurodevelopmental conditions,the molecular and cellular features of the nasal mucosa and the contribution of intranasal nano-drug delivery to overcome them.Then,a comprehensive overview of polymeric nanocarriers investigated to increase drug bioavailability in the brain is introduced.

关键词： neurodegenerative diseases Neurodevelopmental disorders Central nervous system Blood—brain barrier Nano-drug delivery systems Nose-to-brain pathway Intranasal administration Polymeric nanoparticles Polymeric micelles Dendrimers

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Significance of mitochondrial activity in neurogenesis and neurodegenerative diseases

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Neural Regeneration Research 2022年第4期17卷 741-747页

作者： Serra Ozgen Judith Krigman Ruohan Zhang Nuo Sun Departments of Physiology and Cell Biology The Ohio State University Wexner Medical CenterColumbusOHUSA College of Medicine Graduate Research in the Department of NeuroscienceThe Ohio State UniversityColumbusOHUSA Dorothy M.Davis Heart and Lung Research Institute The Ohio State University Wexner Medical CenterColumbusOHUSA College of Pharmacy Department of Graduate ResearchThe Ohio State UniversityColumbusOHUSA

Mitochondria play a multidimensional role in the function and the vitality of the neurological system.From the generation of neural stem cells to the maintenance of neurons and their ultimate demise,mitochondria play a critical role in regulating our neural pathways'homeostasis,a task that is critical to our cognitive health and neurological well-being.Mitochondria provide energy via oxidative phosphorylation for the neurotransmission and generation of an action potential along the neuron's axon.This paper will first review and examine the molecular subtleties of the mitochondria's role in neurogenesis and neuron vitality,as well as outlining the impact of defective mitochondria in neural aging.The authors will then summarize neurodegenerative diseases related to either neurogenesis or homeostatic dysfunction.Because of the significant detriment neurodegenerative diseases have on the quality of life,it is essential to understand their etiology and ongoing molecular mechanics.The mitochondrial role in neurogenesis and neuron vitality is essential.Dissecting and understanding this organelle's role in the genesis and homeostasis of neurons should assist in finding pharmaceutical targets for neurodegenerative diseases.

关键词： Alzheimer's disease autophagy mitochondria mitophagy neural stem cells neurodegenerative diseases neurogenesis Parkin Parkinson's disease PINK1

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Mitochondria targeting drugs for neurodegenerative diseases——Design, mechanism and application

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Acta Pharmaceutica Sinica B 2022年第6期12卷 2778-2789页

作者： Jiajia Xu Wei Du Yunhe Zhao Kahleong Lim Li Lu Chengwu Zhang Lin Li Key Laboratory of Flexible Electronics(KLOFE)&Institute of Advanced Materials(IAM) Jiangsu National Synergetic Innovation Center for Advanced Materials(SICAM)Nanjing Tech University(NanjingTech)Nanjing 211816China Department of Anatomy Shanxi Medical UniversityTaiyuan 030001China Lee Kang Chian School of Medicine Nanyang Technological UniversitySingapore 308232Singapore School of Basic Medical Sciences Shanxi Medical UniversityTaiyuan 030001China The Institute of Flexible Electronics(IFE Future Technologies)Xiamen UniversityXiamen 361005China

neurodegenerative diseases(NDDs) such as Alzheimer’s disease(AD) and Parkinson ’s disease(PD) are a heterogeneous group of disorders characterized by progressive degeneration of neurons.NDDs threaten the lives of millions of people worldwide and regretfully remain incurable.It is well accepted that dysfunction of mitochondria underlies the pathogenesis of NDDs.Dysfunction of mitochondria results in energy depletion,oxidative stress,calcium overloading,caspases activation,which dominates the neuronal death of NDDs.Therefore,mitochondria are the preferred target for intervention of NDDs.So far various mitochondria-targeting drugs have been developed and delightfully some of them demonstrate promising outcome,though there are still some obstacles such as targeting specificity,delivery capacity hindering the drugs development.In present review,we will elaborately address 1) the strategy to design mitochondria targeting drugs,2) the rescue mechanism of respective mitochondria targeting drugs,3) how to evaluate the therapeutic effect.Hopefully this review will provide comprehensive knowledge for understanding how to develop more effective drugs for the treatment of NDDs.

关键词： neurodegenerative diseases Mitochondria Targeting drug Apoptosis Reactive oxygen species Adenosine triphosphate Mitochondrial membrane potential Evaluation

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Correlation of Ferroptosis and Other Types of Cell Death in neurodegenerative diseases

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Neuroscience Bulletin 2022年第8期38卷 938-952页

作者： Xiaoting Dang Xuejie Huan Xixun Du Xi Chen Mingxia Bi Chunling Yan Qian Jiao Hong Jiang Department of Physiology Shandong Provincial Key Laboratory of PathogenesisPrevention of Neurological DisordersState Key Disciplines:PhysiologySchool of Basic MedicineQingdao UniversityQingdao266071China

Ferroptosis is defined as an iron-dependent,non-apoptotic cell death pathway,with specific morphological phenotypes and biochemical changes.There is a growing realization that ferroptosis has significant implications for several neurodegenerative diseases.Even though ferroptosis is different from other forms of programmed death such as apoptosis and autophagic death,they involve a number of common protein molecules.This review focuses on current research on ferroptosis and summarizes the cross-talk among ferroptosis,apoptosis,and autophagy that are implicated in neurodegenerative diseases.We hope that this information provides new ideas for understanding the mechanisms and searching for potential therapeutic approaches and prevention of neurodegenerative diseases.

关键词： Ferroptosis Apoptosis Autophagic death neurodegenerative diseases

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New pathogenic insights from large animal models of neurodegenerative diseases

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Protein & Cell 2022年第10期13卷 707-720页

作者： Peng Yin Shihua Li Xiao-Jiang Li Weili Yang Guangdong Key Laboratory of Non-human Primate Research Guangdong-Hongkong-Macao Institute of CNS RegenerationJinan UniversityGuangzhou 510632China

Animal models are essential for investigating the pathogenesis and developing the treatment of human diseases.Identification of genetic mutations responsible for neurodegenerative diseases has enabled the creation of a large number of small animal models that mimic genetic defects found in the affected individuals.Of the current animal models,rodents with genetic modifications are the most commonly used animal models and provided important insights into pathogenesis.However,most of genetically modified rodent models lack overt neurodegeneration,imposing challenges and obstacles in utilizing them to rigorously test the therapeutic effects on neurodegeneration.Recent studies that used CRISPR/Cas9-targeted large animal(pigs and monkeys)have uncovered important pathological events that resemble neurodegeneration in the patient’s brain but could not be produced in small animal models.Here we highlight the unique nature of large animals to model neurodegenerative diseases as well as the limitations and challenges in establishing large animal models of neurodegenerative diseases,with focus on Huntington disease,Amyotrophic lateral sclerosis,and Parkinson diseases.We also discuss how to use the important pathogenic insights from large animal models to make rodent models more capable of recapitulating important pathological features of neurodegenerative diseases.

关键词： large animal models neurodegenerative diseases CRISPR/Cas9

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Phytochemicals as inhibitors of tumor necrosis factor alpha and neuroinflammatory responses in neurodegenerative diseases

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Neural Regeneration Research 2022年第8期17卷 1675-1684页

作者： Fatemeh Zahedipour Seyede Atefe Hosseini Neil C.Henney George E.Barreto Amirhossein Sahebkar Department of Medical Biotechnology School of MedicineMashhad University of Medical SciencesMashhadIran Student Research Committee Faculty of MedicineMashhad University of Medical SciencesMashhadIran Pharmacy&Biomolecular Sciences Liverpool John Moores UniversityLiverpoolUK Department of Biological Sciences University of LimerickLimerickIreland Health Research Institute University of LimerickLimerickIreland Applied Biomedical Research Center Mashhad University of Medical SciencesMashhadIran Biotechnology Research Center Pharmaceutical Technology InstituteMashhad University of Medical SciencesMashhadIran Polish Mother’s Memorial Hospital Research Institute(PMMHRI) LodzPoland School of Pharmacy Mashhad University of Medical SciencesMashhadIran

Inflammatory processes and proinflammatory cytokines have a key role in the cellular processes of neurodegenerative diseases and are linked to the pathogenesis of functional and mental health disorders.Tumor necrosis factor alpha has been reported to play a major role in the central nervous system in Alzheimer’s disease,Parkinson’s disease and amyotrophic lateral sclerosis and many other neurodegenerative diseases.Therefore,a potent proinflammatory/proapoptotic tumor necrosis factor alpha could be a strong candidate for targeted therapy.Plant derivatives have now become promising candidates as therapeutic agents because of their antioxidant and chemical characteristics,and anti-inflammatory features.Recently,phytochemicals including flavonoids,terpenoids,alkaloids,and lignans have generated interest as tumor necrosis factor alpha inhibitor candidates for a number of diseases involving inflammation within the nervous system.In this review,we discuss how phytochemicals as tumor necrosis factor alpha inhibitors are a therapeutic strategy targeting neurodegeneration.

关键词： brain central nervous system cytokine herbal medicine inflammation neurodegenerative diseases phytochemicals tumor necrosis factor-alpha

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Dendrobium species regulate energy homeostasis in neurodegenerative diseases: a review

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Food Science and Human Wellness 2023年第6期12卷 2151-2174页

作者： Feixuan Wang Jingqiong Wan Yangzhen Liao Shangyu Liu Yuan Wei Zhen Ouyang School of Pharmacy Jiangsu UniversityZhenjiang 212013China Nanjing Institute of Product Quality Inspection Nanjing 210019China School of Food and Biological Engineering Jiangsu UniversityZhenjiang 212013China

Brain energy homeostasis is a vital physiological function in maintaining a balanced internal metabolic environment.The impairment of energy homeostasis is recognized as a key pathophysiological basis for brain metabolic disorders and related neurodegenerative diseases.Dendrobium species(‘Shihu’in Chinese)such as D.officinale,D.huoshanense,D.nobile,D.chrysanthum,D.loddigesii,D.moniliforme,D.gratiosissimum,D.candidum and D.caulis are widely used as traditional Chinese medicines/nutraceuticals to control and treat neurodegenerative disorders.These dietary herbs and their derived compounds possess a variety of biological properties,such as suppression of oxidative stress and neuroinflammation,regulation of energy homeostasis mainly through improving brain mitochondria function,insulin signaling and lipid metabolism.Furthermore,they reduce neurotoxicity,alleviate brain injury and neuropathy,and prevent neurodegenerative conditions including stroke,Alzheimer’s disease,Parkinson’s disease,and Huntington’s disease in humans and/or rodents.Moreover,the nutraceuticals from Dendrobium species promote gut health and aid digestion,which appear to be associated with beneficial effects on brain energy homeostasis.Based on the above-mentioned health benefits associated with Dendrobium species,this work reviews their nutraceutical role in neurodegenerative disorders and further suggests the need to elucidate mechanisms of the underlying molecular actions.

关键词： Dendrobium species Nutraceutical role Energy homeostasis neurodegenerative diseases

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Nanomaterials for neurodegenerative diseases:Molecular mechanisms guided design and applications

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Nano Research 2022年第4期15卷 3299-3322页

作者： Tianzhong Li Xueyan Hou Yu Qi Xiaohan Duan Pengcheng Yan Haoru Zhu Zhongjian Xie Han Zhang Shenzhen International Institute for Biomedical Research Shenzhen 518110China International Collaborative Laboratory of 2D Materials for Optoelectronics Science and Technology of Ministry of Education Institute of Microscale OptoelectronicsShenzhen UniversityShenzhen 518060China School of Pharmaceutical Sciences Wenzhou Medical UniversityWenzhou 325035China Institute of Pediatrics Shenzhen Children’s HospitalShenzhen 518038China

Successful treatment of neurodegenerative diseases(NDDs),including Alzheimer’s disease(AD),Parkinson’s disease(PD),and Huntington’s disease(HD),remains a significant challenge for neurologists due to the undesirable curative outcomes.Apart from surgeries,most drugs are only used to relieve the patients’symptoms without a permanent cure of the disease.The development of novel biomaterials targeting NDDs is greatly hindered by the limited understanding of underlying molecular mechanisms.Considering the difficulties in NDD drug development and clinical trials,a comprehensive and up-to-date review of disease pathogenesis and related novel therapies are needed.In the current article,the basic concepts and pathogenic characteristics of NDDs are firstly illustrated.Following the detailed description of molecular mechanisms underlying three common NDDs,recent advances of drug development based on targeting different pathogenic mechanisms are clarified.Hopefully,this review will be beneficial to address the gap between materials and targeted mechanisms while simultaneously provide suggestions for the future design of precise NDD medicine.

关键词： neurodegenerative diseases molecular mechanisms nanomaterials signaling pathways protein aggregation

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