Pub Date : 2024-12-01Epub Date: 2024-03-01DOI: 10.4103/NRR.NRR-D-23-01677
Maria Ilenia De Bartolo, Daniele Belvisi, Romina Mancinelli, Matteo Costanzo, Claudia Caturano, Giorgio Leodori, Alfredo Berardelli, Giovanni Fabbrini, Giorgio Vivacqua
The search for reliable and easily accessible biomarkers in Parkinson's disease is receiving a growing emphasis, to detect neurodegeneration from the prodromal phase and to enforce disease-modifying therapies. Despite the need for non-invasively accessible biomarkers, the majority of the studies have pointed to cerebrospinal fluid or peripheral biopsies biomarkers, which require invasive collection procedures. Saliva represents an easily accessible biofluid and an incredibly wide source of molecular biomarkers. In the present study, after presenting the morphological and biological bases for looking at saliva in the search of biomarkers for Parkinson's disease, we systematically reviewed the results achieved so far in the saliva of different cohorts of Parkinson's disease patients. A comprehensive literature search on PubMed and SCOPUS led to the discovery of 289 articles. After screening and exclusion, 34 relevant articles were derived for systematic review. Alpha-synuclein, the histopathological hallmark of Parkinson's disease, has been the most investigated Parkinson's disease biomarker in saliva, with oligomeric alpha-synuclein consistently found increased in Parkinson's disease patients in comparison to healthy controls, while conflicting results have been reported regarding the levels of total alpha-synuclein and phosphorylated alpha-synuclein, and few studies described an increased oligomeric alpha-synuclein/total alpha-synuclein ratio in Parkinson's disease. Beyond alpha-synuclein, other biomarkers targeting different molecular pathways have been explored in the saliva of Parkinson's disease patients: total tau, phosphorylated tau, amyloid-β1-42 (pathological protein aggregation biomarkers); DJ-1, heme-oxygenase-1, metabolites (altered energy homeostasis biomarkers); MAPLC-3beta (aberrant proteostasis biomarker); cortisol, tumor necrosis factor-alpha (inflammation biomarkers); DNA methylation, miRNA (DNA/RNA defects biomarkers); acetylcholinesterase activity (synaptic and neuronal network dysfunction biomarkers); Raman spectra, proteome, and caffeine. Despite a few studies investigating biomarkers targeting molecular pathways different from alpha-synuclein in Parkinson's disease, these results should be replicated and observed in studies on larger cohorts, considering the potential role of these biomarkers in determining the molecular variance among Parkinson's disease subtypes. Although the need for standardization in sample collection and processing, salivary-based biomarkers studies have reported encouraging results, calling for large-scale longitudinal studies and multicentric assessments, given the great molecular potentials and the non-invasive accessibility of saliva.
{"title":"A systematic review of salivary biomarkers in Parkinson's disease.","authors":"Maria Ilenia De Bartolo, Daniele Belvisi, Romina Mancinelli, Matteo Costanzo, Claudia Caturano, Giorgio Leodori, Alfredo Berardelli, Giovanni Fabbrini, Giorgio Vivacqua","doi":"10.4103/NRR.NRR-D-23-01677","DOIUrl":"10.4103/NRR.NRR-D-23-01677","url":null,"abstract":"<p><p>The search for reliable and easily accessible biomarkers in Parkinson's disease is receiving a growing emphasis, to detect neurodegeneration from the prodromal phase and to enforce disease-modifying therapies. Despite the need for non-invasively accessible biomarkers, the majority of the studies have pointed to cerebrospinal fluid or peripheral biopsies biomarkers, which require invasive collection procedures. Saliva represents an easily accessible biofluid and an incredibly wide source of molecular biomarkers. In the present study, after presenting the morphological and biological bases for looking at saliva in the search of biomarkers for Parkinson's disease, we systematically reviewed the results achieved so far in the saliva of different cohorts of Parkinson's disease patients. A comprehensive literature search on PubMed and SCOPUS led to the discovery of 289 articles. After screening and exclusion, 34 relevant articles were derived for systematic review. Alpha-synuclein, the histopathological hallmark of Parkinson's disease, has been the most investigated Parkinson's disease biomarker in saliva, with oligomeric alpha-synuclein consistently found increased in Parkinson's disease patients in comparison to healthy controls, while conflicting results have been reported regarding the levels of total alpha-synuclein and phosphorylated alpha-synuclein, and few studies described an increased oligomeric alpha-synuclein/total alpha-synuclein ratio in Parkinson's disease. Beyond alpha-synuclein, other biomarkers targeting different molecular pathways have been explored in the saliva of Parkinson's disease patients: total tau, phosphorylated tau, amyloid-β1-42 (pathological protein aggregation biomarkers); DJ-1, heme-oxygenase-1, metabolites (altered energy homeostasis biomarkers); MAPLC-3beta (aberrant proteostasis biomarker); cortisol, tumor necrosis factor-alpha (inflammation biomarkers); DNA methylation, miRNA (DNA/RNA defects biomarkers); acetylcholinesterase activity (synaptic and neuronal network dysfunction biomarkers); Raman spectra, proteome, and caffeine. Despite a few studies investigating biomarkers targeting molecular pathways different from alpha-synuclein in Parkinson's disease, these results should be replicated and observed in studies on larger cohorts, considering the potential role of these biomarkers in determining the molecular variance among Parkinson's disease subtypes. Although the need for standardization in sample collection and processing, salivary-based biomarkers studies have reported encouraging results, calling for large-scale longitudinal studies and multicentric assessments, given the great molecular potentials and the non-invasive accessibility of saliva.</p>","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11168506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140855230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-03-01DOI: 10.4103/NRR.NRR-D-23-01031
Yuri R Rigo, Radharani Benvenutti, Luis V Portela, Nathan R Strogulski
Regenerative approaches towards neuronal loss following traumatic brain or spinal cord injury have long been considered a dogma in neuroscience and remain a cutting-edge area of research. This is reflected in a large disparity between the number of studies investigating primary and secondary injury as therapeutic targets in spinal cord and traumatic brain injuries. Significant advances in biotechnology may have the potential to reshape the current state-of-the-art and bring focus to primary injury neurotrauma research. Recent studies using neural-glial factor/antigen 2 (NG2) cells indicate that they may differentiate into neurons even in the developed brain. As these cells show great potential to play a regenerative role, studies have been conducted to test various manipulations in neurotrauma models aimed at eliciting a neurogenic response from them. In the present study, we systematically reviewed the experimental protocols and findings described in the scientific literature, which were peer-reviewed original research articles (1) describing preclinical experimental studies, (2) investigating NG2 cells, (3) associated with neurogenesis and neurotrauma, and (4) in vitro and/or in vivo, available in PubMed/MEDLINE, Web of Science or SCOPUS, from 1998 to 2022. Here, we have reviewed a total of 1504 papers, and summarized findings that ultimately suggest that NG2 cells possess an inducible neurogenic potential in animal models and in vitro. We also discriminate findings of NG2 neurogenesis promoted by different pharmacological and genetic approaches over functional and biochemical outcomes of traumatic brain injury and spinal cord injury models, and provide mounting evidence for the potential benefits of manipulated NG2 cell ex vivo transplantation in primary injury treatment. These findings indicate the feasibility of NG2 cell neurogenesis strategies and add new players in the development of therapeutic alternatives for neurotrauma.
{"title":"Neurogenic potential of NG2 in neurotrauma: a systematic review.","authors":"Yuri R Rigo, Radharani Benvenutti, Luis V Portela, Nathan R Strogulski","doi":"10.4103/NRR.NRR-D-23-01031","DOIUrl":"10.4103/NRR.NRR-D-23-01031","url":null,"abstract":"<p><p>Regenerative approaches towards neuronal loss following traumatic brain or spinal cord injury have long been considered a dogma in neuroscience and remain a cutting-edge area of research. This is reflected in a large disparity between the number of studies investigating primary and secondary injury as therapeutic targets in spinal cord and traumatic brain injuries. Significant advances in biotechnology may have the potential to reshape the current state-of-the-art and bring focus to primary injury neurotrauma research. Recent studies using neural-glial factor/antigen 2 (NG2) cells indicate that they may differentiate into neurons even in the developed brain. As these cells show great potential to play a regenerative role, studies have been conducted to test various manipulations in neurotrauma models aimed at eliciting a neurogenic response from them. In the present study, we systematically reviewed the experimental protocols and findings described in the scientific literature, which were peer-reviewed original research articles (1) describing preclinical experimental studies, (2) investigating NG2 cells, (3) associated with neurogenesis and neurotrauma, and (4) in vitro and/or in vivo, available in PubMed/MEDLINE, Web of Science or SCOPUS, from 1998 to 2022. Here, we have reviewed a total of 1504 papers, and summarized findings that ultimately suggest that NG2 cells possess an inducible neurogenic potential in animal models and in vitro. We also discriminate findings of NG2 neurogenesis promoted by different pharmacological and genetic approaches over functional and biochemical outcomes of traumatic brain injury and spinal cord injury models, and provide mounting evidence for the potential benefits of manipulated NG2 cell ex vivo transplantation in primary injury treatment. These findings indicate the feasibility of NG2 cell neurogenesis strategies and add new players in the development of therapeutic alternatives for neurotrauma.</p>","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11168526/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140864539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-03-01DOI: 10.4103/NRR.NRR-D-23-01490
Xiaowen Xu, Xinxin Wang, Li Zhang, Yiming Jin, Lili Li, Meifang Jin, Lianyong Li, Hong Ni
JOURNAL/nrgr/04.03/01300535-202412000-00031/figure1/v/2024-04-08T165401Z/r/image-tiff Neonatal hypoxic-ischemic brain injury is the main cause of hypoxic-ischemic encephalopathy and cerebral palsy. Currently, there are few effective clinical treatments for neonatal hypoxic-ischemic brain injury. Here, we investigated the neuroprotective and molecular mechanisms of exogenous nicotinamide adenine dinucleotide, which can protect against hypoxic injury in adulthood, in a mouse model of neonatal hypoxic-ischemic brain injury. In this study, nicotinamide adenine dinucleotide (5 mg/kg) was intraperitoneally administered 30 minutes before surgery and every 24 hours thereafter. The results showed that nicotinamide adenine dinucleotide treatment improved body weight, brain structure, adenosine triphosphate levels, oxidative damage, neurobehavioral test outcomes, and seizure threshold in experimental mice. Tandem mass tag proteomics revealed that numerous proteins were altered after nicotinamide adenine dinucleotide treatment in hypoxic-ischemic brain injury mice. Parallel reaction monitoring and western blotting confirmed changes in the expression levels of proteins including serine (or cysteine) peptidase inhibitor, clade A, member 3N, fibronectin 1, 5'-nucleotidase, cytosolic IA, microtubule associated protein 2, and complexin 2. Proteomics analyses showed that nicotinamide adenine dinucleotide ameliorated hypoxic-ischemic injury through inflammation-related signaling pathways (e.g., nuclear factor-kappa B, mitogen-activated protein kinase, and phosphatidylinositol 3 kinase/protein kinase B). These findings suggest that nicotinamide adenine dinucleotide treatment can improve neurobehavioral phenotypes in hypoxic-ischemic brain injury mice through inflammation-related pathways.
{"title":"Nicotinamide adenine dinucleotide treatment confers resistance to neonatal ischemia and hypoxia: effects on neurobehavioral phenotypes.","authors":"Xiaowen Xu, Xinxin Wang, Li Zhang, Yiming Jin, Lili Li, Meifang Jin, Lianyong Li, Hong Ni","doi":"10.4103/NRR.NRR-D-23-01490","DOIUrl":"10.4103/NRR.NRR-D-23-01490","url":null,"abstract":"<p><p>JOURNAL/nrgr/04.03/01300535-202412000-00031/figure1/v/2024-04-08T165401Z/r/image-tiff Neonatal hypoxic-ischemic brain injury is the main cause of hypoxic-ischemic encephalopathy and cerebral palsy. Currently, there are few effective clinical treatments for neonatal hypoxic-ischemic brain injury. Here, we investigated the neuroprotective and molecular mechanisms of exogenous nicotinamide adenine dinucleotide, which can protect against hypoxic injury in adulthood, in a mouse model of neonatal hypoxic-ischemic brain injury. In this study, nicotinamide adenine dinucleotide (5 mg/kg) was intraperitoneally administered 30 minutes before surgery and every 24 hours thereafter. The results showed that nicotinamide adenine dinucleotide treatment improved body weight, brain structure, adenosine triphosphate levels, oxidative damage, neurobehavioral test outcomes, and seizure threshold in experimental mice. Tandem mass tag proteomics revealed that numerous proteins were altered after nicotinamide adenine dinucleotide treatment in hypoxic-ischemic brain injury mice. Parallel reaction monitoring and western blotting confirmed changes in the expression levels of proteins including serine (or cysteine) peptidase inhibitor, clade A, member 3N, fibronectin 1, 5'-nucleotidase, cytosolic IA, microtubule associated protein 2, and complexin 2. Proteomics analyses showed that nicotinamide adenine dinucleotide ameliorated hypoxic-ischemic injury through inflammation-related signaling pathways (e.g., nuclear factor-kappa B, mitogen-activated protein kinase, and phosphatidylinositol 3 kinase/protein kinase B). These findings suggest that nicotinamide adenine dinucleotide treatment can improve neurobehavioral phenotypes in hypoxic-ischemic brain injury mice through inflammation-related pathways.</p>","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11168517/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140866139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-03-01DOI: 10.4103/NRR.NRR-D-23-01723
Balázs Pál
Slow inward currents are known as neuronal excitatory currents mediated by glutamate release and activation of neuronal extrasynaptic N-methyl-D-aspartate receptors with the contribution of astrocytes. These events are significantly slower than the excitatory postsynaptic currents. Parameters of slow inward currents are determined by several factors including the mechanisms of astrocytic activation and glutamate release, as well as the diffusion pathways from the release site towards the extrasynaptic receptors. Astrocytes are stimulated by neuronal network activity, which in turn excite neurons, forming an astrocyte-neuron feedback loop. Mostly as a consequence of brain edema, astrocytic swelling can also induce slow inward currents under pathological conditions. There is a growing body of evidence on the roles of slow inward currents on a single neuron or local network level. These events often occur in synchrony on neurons located in the same astrocytic domain. Besides synchronization of neuronal excitability, slow inward currents also set synaptic strength via eliciting timing-dependent synaptic plasticity. In addition, slow inward currents are also subject to non-synaptic plasticity triggered by long-lasting stimulation of the excitatory inputs. Of note, there might be important region-specific differences in the roles and actions triggering slow inward currents. In greater networks, the pathophysiological roles of slow inward currents can be better understood than physiological ones. Slow inward currents are identified in the pathophysiological background of autism, as slow inward currents drive early hypersynchrony of the neural networks. Slow inward currents are significant contributors to paroxysmal depolarizational shifts/interictal spikes. These events are related to epilepsy, but also found in Alzheimer's disease, Parkinson's disease, and stroke, leading to the decline of cognitive functions. Events with features overlapping with slow inward currents (excitatory, N-methyl-D-aspartate-receptor mediated currents with astrocytic contribution) as ischemic currents and spreading depolarization also have a well-known pathophysiological role in worsening consequences of stroke, traumatic brain injury, or epilepsy. One might assume that slow inward currents occurring with low frequency under physiological conditions might contribute to synaptic plasticity and memory formation. However, to state this, more experimental evidence from greater neuronal networks or the level of the individual is needed. In this review, I aimed to summarize findings on slow inward currents and to speculate on the potential functions of it.
{"title":"On the functions of astrocyte-mediated neuronal slow inward currents.","authors":"Balázs Pál","doi":"10.4103/NRR.NRR-D-23-01723","DOIUrl":"10.4103/NRR.NRR-D-23-01723","url":null,"abstract":"<p><p>Slow inward currents are known as neuronal excitatory currents mediated by glutamate release and activation of neuronal extrasynaptic N-methyl-D-aspartate receptors with the contribution of astrocytes. These events are significantly slower than the excitatory postsynaptic currents. Parameters of slow inward currents are determined by several factors including the mechanisms of astrocytic activation and glutamate release, as well as the diffusion pathways from the release site towards the extrasynaptic receptors. Astrocytes are stimulated by neuronal network activity, which in turn excite neurons, forming an astrocyte-neuron feedback loop. Mostly as a consequence of brain edema, astrocytic swelling can also induce slow inward currents under pathological conditions. There is a growing body of evidence on the roles of slow inward currents on a single neuron or local network level. These events often occur in synchrony on neurons located in the same astrocytic domain. Besides synchronization of neuronal excitability, slow inward currents also set synaptic strength via eliciting timing-dependent synaptic plasticity. In addition, slow inward currents are also subject to non-synaptic plasticity triggered by long-lasting stimulation of the excitatory inputs. Of note, there might be important region-specific differences in the roles and actions triggering slow inward currents. In greater networks, the pathophysiological roles of slow inward currents can be better understood than physiological ones. Slow inward currents are identified in the pathophysiological background of autism, as slow inward currents drive early hypersynchrony of the neural networks. Slow inward currents are significant contributors to paroxysmal depolarizational shifts/interictal spikes. These events are related to epilepsy, but also found in Alzheimer's disease, Parkinson's disease, and stroke, leading to the decline of cognitive functions. Events with features overlapping with slow inward currents (excitatory, N-methyl-D-aspartate-receptor mediated currents with astrocytic contribution) as ischemic currents and spreading depolarization also have a well-known pathophysiological role in worsening consequences of stroke, traumatic brain injury, or epilepsy. One might assume that slow inward currents occurring with low frequency under physiological conditions might contribute to synaptic plasticity and memory formation. However, to state this, more experimental evidence from greater neuronal networks or the level of the individual is needed. In this review, I aimed to summarize findings on slow inward currents and to speculate on the potential functions of it.</p>","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11168512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140869535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-04-08DOI: 10.4103/NRR.NRR-D-24-00234
{"title":"Corrigendum: Genistein protects hippocampal neurons against injury by regulating calcium/calmodulin dependent protein kinase IV protein levels in Alzheimer's disease model rats.","authors":"","doi":"10.4103/NRR.NRR-D-24-00234","DOIUrl":"10.4103/NRR.NRR-D-24-00234","url":null,"abstract":"","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11168518/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140849374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-03-01DOI: 10.4103/NRR.NRR-D-23-01624
Xin Yi Ng, Mian Cao
Parkinson's disease is characterized by the selective degeneration of dopamine neurons in the nigrostriatal pathway and dopamine deficiency in the striatum. The precise reasons behind the specific degeneration of these dopamine neurons remain largely elusive. Genetic investigations have identified over 20 causative PARK genes and 90 genomic risk loci associated with both familial and sporadic Parkinson's disease. Notably, several of these genes are linked to the synaptic vesicle recycling process, particularly the clathrin-mediated endocytosis pathway. This suggests that impaired synaptic vesicle recycling might represent an early feature of Parkinson's disease, followed by axonal degeneration and the eventual loss of dopamine cell bodies in the midbrain via a "dying back" mechanism. Recently, several new animal and cellular models with Parkinson's disease-linked mutations affecting the endocytic pathway have been created and extensively characterized. These models faithfully recapitulate certain Parkinson's disease-like features at the animal, circuit, and cellular levels, and exhibit defects in synaptic membrane trafficking, further supporting the findings from human genetics and clinical studies. In this review, we will first summarize the cellular and molecular findings from the models of two Parkinson's disease-linked clathrin uncoating proteins: auxilin (DNAJC6/PARK19) and synaptojanin 1 (SYNJ1/PARK20). The mouse models carrying these two PARK gene mutations phenocopy each other with specific dopamine terminal pathology and display a potent synergistic effect. Subsequently, we will delve into the involvement of several clathrin-mediated endocytosis-related proteins (GAK, endophilin A1, SAC2/INPP5F, synaptotagmin-11), identified as Parkinson's disease risk factors through genome-wide association studies, in Parkinson's disease pathogenesis. We will also explore the direct or indirect roles of some common Parkinson's disease-linked proteins (alpha-synuclein (PARK1/4), Parkin (PARK2), and LRRK2 (PARK8)) in synaptic endocytic trafficking. Additionally, we will discuss the emerging novel functions of these endocytic proteins in downstream membrane traffic pathways, particularly autophagy. Given that synaptic dysfunction is considered as an early event in Parkinson's disease, a deeper understanding of the cellular mechanisms underlying synaptic vesicle endocytic trafficking may unveil novel targets for early diagnosis and the development of interventional therapies for Parkinson's disease. Future research should aim to elucidate why generalized synaptic endocytic dysfunction leads to the selective degeneration of nigrostriatal dopamine neurons in Parkinson's disease.
帕金森病的特征是黑质通路的多巴胺神经元选择性变性和纹状体多巴胺缺乏。这些多巴胺神经元发生特异性变性的确切原因在很大程度上仍然难以捉摸。遗传学研究发现,有 20 多个 PARK 致病基因和 90 个基因组风险位点与家族性和散发性帕金森病有关。值得注意的是,其中几个基因与突触囊泡循环过程有关,特别是凝胶酶介导的内吞途径。这表明,突触囊泡回收功能受损可能是帕金森病的早期特征,随后会出现轴突变性,并通过 "死亡回流 "机制最终导致中脑多巴胺细胞体丧失。最近,一些与帕金森病相关的、影响内吞途径突变的新动物和细胞模型被制作出来,并被广泛鉴定。这些模型在动物、回路和细胞水平上忠实地再现了某些帕金森病样特征,并表现出突触膜贩运缺陷,进一步支持了人类遗传学和临床研究的发现。在这篇综述中,我们将首先总结与帕金森病相关的两种凝集素疏附蛋白:辅蛋白(DNAJC6/PARK19)和突触素 1(SYNJ1/PARK20)模型的细胞和分子研究结果。携带这两种 PARK 基因突变的小鼠模型在特定多巴胺末端病理学上相互表征,并显示出强大的协同效应。随后,我们将深入研究几种凝集素介导的内吞相关蛋白(GAK、嗜内蛋白 A1、SAC2/INPP5F、synaptotagmin-11)在帕金森病发病机制中的参与情况,这些蛋白通过全基因组关联研究被确定为帕金森病风险因子。我们还将探讨一些常见的帕金森病相关蛋白(α-突触核蛋白(PARK1/4)、Parkin(PARK2)和 LRRK2(PARK8))在突触内细胞贩运中的直接或间接作用。此外,我们还将讨论这些内吞蛋白在下游膜运输途径(尤其是自噬)中新出现的功能。鉴于突触功能障碍被认为是帕金森病的早期症状,深入了解突触囊泡内吞转的细胞机制可能会为帕金森病的早期诊断和干预性疗法的开发揭示新的靶点。未来的研究应致力于阐明为什么普遍的突触内吞功能障碍会导致帕金森病患者黑质多巴胺神经元的选择性变性。
{"title":"Dysfunction of synaptic endocytic trafficking in Parkinson's disease.","authors":"Xin Yi Ng, Mian Cao","doi":"10.4103/NRR.NRR-D-23-01624","DOIUrl":"10.4103/NRR.NRR-D-23-01624","url":null,"abstract":"<p><p>Parkinson's disease is characterized by the selective degeneration of dopamine neurons in the nigrostriatal pathway and dopamine deficiency in the striatum. The precise reasons behind the specific degeneration of these dopamine neurons remain largely elusive. Genetic investigations have identified over 20 causative PARK genes and 90 genomic risk loci associated with both familial and sporadic Parkinson's disease. Notably, several of these genes are linked to the synaptic vesicle recycling process, particularly the clathrin-mediated endocytosis pathway. This suggests that impaired synaptic vesicle recycling might represent an early feature of Parkinson's disease, followed by axonal degeneration and the eventual loss of dopamine cell bodies in the midbrain via a \"dying back\" mechanism. Recently, several new animal and cellular models with Parkinson's disease-linked mutations affecting the endocytic pathway have been created and extensively characterized. These models faithfully recapitulate certain Parkinson's disease-like features at the animal, circuit, and cellular levels, and exhibit defects in synaptic membrane trafficking, further supporting the findings from human genetics and clinical studies. In this review, we will first summarize the cellular and molecular findings from the models of two Parkinson's disease-linked clathrin uncoating proteins: auxilin (DNAJC6/PARK19) and synaptojanin 1 (SYNJ1/PARK20). The mouse models carrying these two PARK gene mutations phenocopy each other with specific dopamine terminal pathology and display a potent synergistic effect. Subsequently, we will delve into the involvement of several clathrin-mediated endocytosis-related proteins (GAK, endophilin A1, SAC2/INPP5F, synaptotagmin-11), identified as Parkinson's disease risk factors through genome-wide association studies, in Parkinson's disease pathogenesis. We will also explore the direct or indirect roles of some common Parkinson's disease-linked proteins (alpha-synuclein (PARK1/4), Parkin (PARK2), and LRRK2 (PARK8)) in synaptic endocytic trafficking. Additionally, we will discuss the emerging novel functions of these endocytic proteins in downstream membrane traffic pathways, particularly autophagy. Given that synaptic dysfunction is considered as an early event in Parkinson's disease, a deeper understanding of the cellular mechanisms underlying synaptic vesicle endocytic trafficking may unveil novel targets for early diagnosis and the development of interventional therapies for Parkinson's disease. Future research should aim to elucidate why generalized synaptic endocytic dysfunction leads to the selective degeneration of nigrostriatal dopamine neurons in Parkinson's disease.</p>","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11168511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140864651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JOURNAL/nrgr/04.03/01300535-202419110-00029/figure1/v/2024-03-08T184507Z/r/image-tiff Our previous study has demonstrated that lnc_000048 is upregulated in large-artery atherosclerotic stroke and promotes atherosclerosis in ApoE-/- mice. However, little is known about the role of lnc_000048 in classically activated macrophage (M1) polarization. In this study, we established THP-1-derived testing state macrophages (M0), M1 macrophages, and alternately activated macrophages (M2). Real-time fluorescence quantitative PCR was used to verify the expression of marker genes and the expression of lnc_000048 in macrophages. Flow cytometry was used to detect phenotypic proteins (CD11b, CD38, CD80). We generated cell lines with lentivirus-mediated upregulation or downregulation of lnc_000048. Flow cytometry, western blot, and real-time fluorescence quantitative PCR results showed that down-regulation of lnc_000048 reduced M1 macrophage polarization and the inflammation response, while over-expression of lnc_000048 led to the opposite effect. Western blot results indicated that lnc_000048 enhanced the activation of the STAT1 pathway and mediated the M1 macrophage polarization. Moreover, catRAPID prediction, RNA-pull down, and mass spectrometry were used to identify and screen the protein kinase RNA-activated (PKR), then catRAPID and RPIseq were used to predict the binding ability of lnc_000048 to PKR. Immunofluorescence (IF)-RNA fluorescence in situ hybridization (FISH) double labeling was performed to verify the subcellular colocalization of lnc_000048 and PKR in the cytoplasm of M1 macrophage. We speculate that lnc_000048 may form stem-loop structure-specific binding and activate PKR by inducing its phosphorylation, leading to activation of STAT1 phosphorylation and thereby enhancing STAT1 pathway-mediated polarization of THP-1 macrophages to M1 and inflammatory factor expression. Taken together, these results reveal that the lnc_000048/PKR/STAT1 axis plays a crucial role in the polarization of M1 macrophages and may be a novel therapeutic target for atherosclerosis alleviation in stroke.
{"title":"Atherosis-associated lnc_000048 activates PKR to enhance STAT1-mediated polarization of THP-1 macrophages to M1 phenotype.","authors":"Yuanyuan Ding, Yu Sun, Hongyan Wang, Hongqin Zhao, Ruihua Yin, Meng Zhang, Xudong Pan, Xiaoyan Zhu","doi":"10.4103/NRR.NRR-D-23-01355","DOIUrl":"10.4103/NRR.NRR-D-23-01355","url":null,"abstract":"<p><p>JOURNAL/nrgr/04.03/01300535-202419110-00029/figure1/v/2024-03-08T184507Z/r/image-tiff Our previous study has demonstrated that lnc_000048 is upregulated in large-artery atherosclerotic stroke and promotes atherosclerosis in ApoE-/- mice. However, little is known about the role of lnc_000048 in classically activated macrophage (M1) polarization. In this study, we established THP-1-derived testing state macrophages (M0), M1 macrophages, and alternately activated macrophages (M2). Real-time fluorescence quantitative PCR was used to verify the expression of marker genes and the expression of lnc_000048 in macrophages. Flow cytometry was used to detect phenotypic proteins (CD11b, CD38, CD80). We generated cell lines with lentivirus-mediated upregulation or downregulation of lnc_000048. Flow cytometry, western blot, and real-time fluorescence quantitative PCR results showed that down-regulation of lnc_000048 reduced M1 macrophage polarization and the inflammation response, while over-expression of lnc_000048 led to the opposite effect. Western blot results indicated that lnc_000048 enhanced the activation of the STAT1 pathway and mediated the M1 macrophage polarization. Moreover, catRAPID prediction, RNA-pull down, and mass spectrometry were used to identify and screen the protein kinase RNA-activated (PKR), then catRAPID and RPIseq were used to predict the binding ability of lnc_000048 to PKR. Immunofluorescence (IF)-RNA fluorescence in situ hybridization (FISH) double labeling was performed to verify the subcellular colocalization of lnc_000048 and PKR in the cytoplasm of M1 macrophage. We speculate that lnc_000048 may form stem-loop structure-specific binding and activate PKR by inducing its phosphorylation, leading to activation of STAT1 phosphorylation and thereby enhancing STAT1 pathway-mediated polarization of THP-1 macrophages to M1 and inflammatory factor expression. Taken together, these results reveal that the lnc_000048/PKR/STAT1 axis plays a crucial role in the polarization of M1 macrophages and may be a novel therapeutic target for atherosclerosis alleviation in stroke.</p>","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11090429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140207338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01Epub Date: 2024-03-08DOI: 10.4103/NRR.NRR-D-24-00178
{"title":"Retraction: Regulation of extracellular signal-regulated kinase 1/2 influences hippocampal neuronal survival in a rat model of diabetic cerebral ischemia.","authors":"","doi":"10.4103/NRR.NRR-D-24-00178","DOIUrl":"10.4103/NRR.NRR-D-24-00178","url":null,"abstract":"","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11090420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140207352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01Epub Date: 2024-01-31DOI: 10.4103/NRR.NRR-D-23-01676
Felix Kohle, Michael Schroeter
{"title":"Neuronal trafficking as a key to functional recovery in immune-mediated neuropathies.","authors":"Felix Kohle, Michael Schroeter","doi":"10.4103/NRR.NRR-D-23-01676","DOIUrl":"10.4103/NRR.NRR-D-23-01676","url":null,"abstract":"","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11090439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140207346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}