Progress in Neurobiology最新文献

{"title":"Grid codes underlie multiple cognitive maps in the human brain","authors":"Dong Chen ,&nbsp;Nikolai Axmacher ,&nbsp;Liang Wang","doi":"10.1016/j.pneurobio.2024.102569","DOIUrl":"10.1016/j.pneurobio.2024.102569","url":null,"abstract":"<div><p>Grid cells fire at multiple positions that organize the vertices of equilateral triangles tiling a 2D space and are well studied in rodents. The last decade witnessed rapid progress in two other research lines on grid codes—empirical studies on distributed human grid-like representations in physical and multiple non-physical spaces, and cognitive computational models addressing the function of grid cells based on principles of efficient and predictive coding. Here, we review the progress in these fields and integrate these lines into a systematic organization. We also discuss the coordinate mechanisms of grid codes in the human entorhinal cortex and medial prefrontal cortex and their role in neurological and psychiatric diseases.</p></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"233 ","pages":"Article 102569"},"PeriodicalIF":6.7,"publicationDate":"2024-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139469587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tdrd3-null mice show post-transcriptional and behavioral impairments associated with neurogenesis and synaptic plasticity","authors":"Xingliang Zhu ,&nbsp;Yuyoung Joo ,&nbsp;Simone Bossi ,&nbsp;Ross A. McDevitt ,&nbsp;Aoji Xie ,&nbsp;Yue Wang ,&nbsp;Yutong Xue ,&nbsp;Shuaikun Su ,&nbsp;Seung Kyu Lee ,&nbsp;Nirnath Sah ,&nbsp;Shiliang Zhang ,&nbsp;Rong Ye ,&nbsp;Alejandro Pinto ,&nbsp;Yongqing Zhang ,&nbsp;Kimi Araki ,&nbsp;Masatake Araki ,&nbsp;Marisela Morales ,&nbsp;Mark P. Mattson ,&nbsp;Henriette van Praag ,&nbsp;Weidong Wang","doi":"10.1016/j.pneurobio.2024.102568","DOIUrl":"10.1016/j.pneurobio.2024.102568","url":null,"abstract":"<div><p>The <u>Top</u>oisomerase <u>3B</u> (Top3b) - <u>T</u>u<u>d</u>o<u>r d</u>omain containing <u>3</u><span> (Tdrd3) protein complex is the only dual-activity topoisomerase complex that can alter both DNA and RNA topology in animals. </span><em>TOP3B</em><span> mutations in humans are associated with schizophrenia<span><span>, autism and </span>cognitive disorders; and </span></span><em>Top3b</em><span>-null mice exhibit several phenotypes observed in animal models of psychiatric and cognitive disorders, including impaired cognitive and emotional behaviors<span>, aberrant neurogenesis<span> and synaptic plasticity, and transcriptional defects. Similarly, human </span></span></span><em>TDRD3</em> genomic variants have been associated with schizophrenia, verbal short-term memory and educational attainment. However, the importance of <em>Tdrd3</em> in normal brain function has not been examined in animal models. Here we generated a <em>Tdrd3</em>-null mouse strain and demonstrate that these mice display both shared and unique defects when compared to <em>Top3b-</em>null mice. Shared defects were observed in cognitive behaviors, synaptic plasticity, adult neurogenesis, newborn neuron morphology, and neuronal activity-dependent transcription; whereas defects unique to <em>Tdrd3</em><span><span>-deficient mice include hyperactivity, changes in anxiety-like behaviors, olfaction<span>, increased new neuron complexity, and reduced myelination. Interestingly, multiple genes critical for </span></span>neurodevelopment and cognitive function exhibit reduced levels in mature but not nascent transcripts. We infer that the entire Top3b-Tdrd3 complex is essential for normal brain function, and that defective post-transcriptional regulation could contribute to cognitive and psychiatric disorders.</span></p></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"233 ","pages":"Article 102568"},"PeriodicalIF":6.7,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139422235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dissecting neural circuits from rostral ventromedial medulla to spinal trigeminal nucleus bidirectionally modulating craniofacial mechanical sensitivity","authors":"Yang Xue,&nbsp;Siyi Mo,&nbsp;Yuan Li,&nbsp;Ye Cao,&nbsp;Xiaoxiang Xu,&nbsp;Qiufei Xie","doi":"10.1016/j.pneurobio.2023.102561","DOIUrl":"10.1016/j.pneurobio.2023.102561","url":null,"abstract":"<div><p><span><span><span>Chronic craniofacial pain is intractable and its mechanisms remain unclarified. The rostral ventromedial medulla (RVM) plays a crucial role in descending pain facilitation and inhibition. It is unclear how the descending circuits from the RVM to </span>spinal trigeminal nucleus (Sp5) are organized to bidirectionally modulate craniofacial </span>nociception. We used viral tracing, </span><em>in vivo</em><span><span> optogenetics, </span>calcium signaling<span> recording, and chemogenetic manipulations to investigate the structure and function of RVM-Sp5 circuits. We found that most RVM neurons projecting to Sp5 were GABAergic or glutamatergic and facilitated or inhibited craniofacial nociception, respectively. Both GABAergic interneurons<span> and glutamatergic projection neurons in Sp5 received RVM inputs: the former were antinociceptive, whereas the latter were pronociceptive. Furthermore, we demonstrated activation of both GABAergic and glutamatergic Sp5 neurons receiving RVM inputs in inflammation- or dysfunction-induced masseter hyperalgesia. Activating GABAergic Sp5 neurons or inhibiting glutamatergic Sp5 neurons that receive RVM projections reversed masseter hyperalgesia. Our study identifies specific cell types and projections of RVM-Sp5 circuits involved in facilitating or inhibiting craniofacial nociception respectively. Selective manipulation of RVM-Sp5 circuits can be used as potential treatment strategy to relieve chronic craniofacial muscle pain.</span></span></span></p></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"232 ","pages":"Article 102561"},"PeriodicalIF":6.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139015281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ABHD6 drives endocytosis of AMPA receptors to regulate synaptic plasticity and learning flexibility","authors":"Mengping Wei ,&nbsp;Lei Yang ,&nbsp;Feng Su ,&nbsp;Ying Liu ,&nbsp;Xinyi Zhao ,&nbsp;Lin Luo ,&nbsp;Xinyue Sun ,&nbsp;Sen Liu ,&nbsp;Zhaoqi Dong ,&nbsp;Yong Zhang ,&nbsp;Yun Stone Shi ,&nbsp;Jing Liang ,&nbsp;Chen Zhang","doi":"10.1016/j.pneurobio.2023.102559","DOIUrl":"10.1016/j.pneurobio.2023.102559","url":null,"abstract":"<div><p><span>Trafficking of α‐Amino‐3–hydroxy‐5–methylisoxazole‐4–propionic acid (AMPA) receptors (AMPARs), mediated by AMPAR<span> interacting proteins, enabled neurons to maintain tuning capabilities at rest or active state. α/β-Hydrolase domain-containing 6 (ABHD6), an endocannabinoid<span> hydrolase, was an AMPAR auxiliary subunit found to negatively regulate the surface delivery of AMPARs. While ABHD6 was found to prevent AMPAR tetramerization in endoplasmic reticulum, ABHD6 was also reported to localize at postsynaptic site. Yet, the role of ABHD6 interacting with AMPAR at postsynaptic site, and the physiological significance of ABHD6 regulating AMPAR trafficking remains elusive. Here, we generated the ABHD6 knockout (ABHD6</span></span></span>^KO<span><span>) mice and found that deletion of ABHD6 selectively enhanced AMPAR-mediated basal synaptic responses and the surface expression of postsynaptic AMPARs. Furthermore, we found that loss of ABHD6 impaired hippocampal long-term depression (LTD) and synaptic downscaling in hippocampal synapses. AMPAR internalization assays revealed that ABHD6 was essential for neuronal activity-dependent </span>endocytosis of surface AMPARs, which is independent of ABHD6's hydrolase activity. The defects of AMPAR endocytosis and LTD are expressed as deficits in learning flexibility in ABHD6</span>^KO mice. Collectively, we demonstrated that ABHD6 is an endocytic accessory protein promoting AMPAR endocytosis, thereby contributes to the formation of LTD, synaptic downscaling and reversal learning.</p></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"233 ","pages":"Article 102559"},"PeriodicalIF":6.7,"publicationDate":"2023-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139070476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase of neural oscillations as a reference frame for attention-based routing in visual cortex","authors":"Ehsan Aboutorabi ,&nbsp;Sonia Baloni Ray ,&nbsp;Daniel Kaping ,&nbsp;Farhad Shahbazi ,&nbsp;Stefan Treue ,&nbsp;Moein Esghaei","doi":"10.1016/j.pneurobio.2023.102563","DOIUrl":"10.1016/j.pneurobio.2023.102563","url":null,"abstract":"<div><p>Selective attention allows the brain to efficiently process the image projected onto the retina, selectively focusing neural processing resources on behaviorally relevant visual information. While previous studies have documented the crucial role of the action potential rate of single neurons in relaying such information, little is known about how the activity of single neurons relative to their neighboring network contributes to the efficient representation of attended stimuli and transmission of this information to downstream areas. Here, we show in the dorsal visual pathway of monkeys (medial superior temporal area) that neurons fire spikes preferentially at a specific phase of the ongoing population beta (∼20 Hz) oscillations of the surrounding local network. This preferred spiking phase shifts towards a later phase when monkeys selectively attend towards (rather than away from) the receptive field of the neuron. This shift of the locking phase is positively correlated with the speed at which animals report a visual change. Furthermore, our computational modeling suggests that neural networks can manipulate the preferred phase of coupling by imposing differential synaptic delays on postsynaptic potentials. This distinction between the locking phase of neurons activated by the spatially attended stimulus vs. that of neurons activated by the unattended stimulus, may enable the neural system to discriminate relevant from irrelevant sensory inputs and consequently filter out distracting stimuli information by aligning the spikes which convey relevant/irrelevant information to distinct phases linked to periods of better/worse perceptual sensitivity for higher cortices. This strategy may be used to reserve the narrow windows of highest perceptual efficacy to the processing of the most behaviorally relevant information, ensuring highly efficient responses to attended sensory events.</p></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"233 ","pages":"Article 102563"},"PeriodicalIF":6.7,"publicationDate":"2023-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301008223001648/pdfft?md5=f287bf2456194346458c7bb8762f746c&pid=1-s2.0-S0301008223001648-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139032518","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}

{"title":"Traumatic brain injury derived pathological tau polymorphs induce the distinct propagation pattern and neuroinflammatory response in wild type mice","authors":"Nicha Puangmalai ,&nbsp;Nemil Bhatt ,&nbsp;Alice Bittar ,&nbsp;Cynthia Jerez ,&nbsp;Nikita Shchankin ,&nbsp;Rakez Kayed","doi":"10.1016/j.pneurobio.2023.102562","DOIUrl":"10.1016/j.pneurobio.2023.102562","url":null,"abstract":"<div><p>The misfolding and aggregation of the tau protein into neurofibrillary tangles constitutes a central feature of tauopathies. Traumatic brain injury (TBI) has emerged as a potential risk factor, triggering the onset and progression of tauopathies. Our previous research revealed distinct polymorphisms in soluble tau oligomers originating from single versus repetitive mild TBIs. However, the mechanisms orchestrating the dissemination of TBI brain-derived tau polymorphs (TBI-BDTPs) remain elusive. In this study, we explored whether TBI-BDTPs could initiate pathological tau formation, leading to distinct pathogenic trajectories. Wild-type mice were exposed to TBI-BDTPs from sham, single-blast (SB), or repeated-blast (RB) conditions, and their memory function was assessed through behavioral assays at 2- and 8-month post-injection. Our findings revealed that RB-BDTPs induced cognitive and motor deficits, concurrently fostering the emergence of toxic tau aggregates within the injected hippocampus. Strikingly, this tau pathology propagated to cortical layers, intensifying over time. Importantly, RB-BDTP-exposed animals displayed heightened glial cell activation, NLRP3 inflammasome formation, and increased TBI biomarkers, particularly triggering the aggregation of S100B, which is indicative of a neuroinflammatory response. Collectively, our results shed light on the intricate mechanisms underlying TBI-BDTP-induced tau pathology and its association with neuroinflammatory processes. This investigation enhances our understanding of tauopathies and their interplay with neurodegenerative and inflammatory pathways following traumatic brain injury.</p></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"232 ","pages":"Article 102562"},"PeriodicalIF":6.7,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301008223001636/pdfft?md5=b077c73ebac19a0192fc620dcc67a4f0&pid=1-s2.0-S0301008223001636-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138885982","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}

{"title":"FAME4-associating YEATS2 knockdown impairs dopaminergic synaptic integrity and leads to seizure-like behaviours in Drosophila melanogaster","authors":"Luca Lo Piccolo ,&nbsp;Ranchana Yeewa ,&nbsp;Sureena Pohsa ,&nbsp;Titaree Yamsri ,&nbsp;Daniel Calovi ,&nbsp;Jutarop Phetcharaburanin ,&nbsp;Manida Suksawat ,&nbsp;Thanaporn Kulthawatsiri ,&nbsp;Vorasuk Shotelersuk ,&nbsp;Salinee Jantrapirom","doi":"10.1016/j.pneurobio.2023.102558","DOIUrl":"10.1016/j.pneurobio.2023.102558","url":null,"abstract":"<div><p><span>Familial adult myoclonus epilepsy (FAME) is a neurological disorder caused by a </span><em>TTTTA/TTTCA</em> intronic repeat expansion. FAME4 is one of the six types of FAME that results from the repeat expansion in the first intron of the gene <em>YEATS2</em>. Although the RNA toxicity is believed to be the primary mechanism underlying FAME, the role of genes where repeat expansions reside is still unclear, particularly in the case of YEATS2 in neurons. This study used <em>Drosophila</em> to explore the effects of reducing <em>YEATS2</em> expression. Two pan-neuronally driven <em>dsDNA</em> were used for knockdown of <em>Drosophila YEATS2</em> (<em>dYEATS2</em>), and the resulting molecular and behavioural outcomes were evaluated. <em>Drosophila</em> with reduced <em>dYEATS2</em> expression exhibited decreased tolerance to acute stress, disturbed locomotion, abnormal social behaviour, and decreased motivated activity. Additionally, reducing <em>dYEATS2</em> expression negatively affected <span><em>tyrosine hydroxylase</em></span> (<em>TH</em><span>) gene expression, resulting in decreased dopamine biosynthesis. Remarkably, seizure-like behaviours induced by knocking down </span><em>dYEATS2</em><span> were rescued by the administration of L-DOPA. This study reveals a novel role of YEATS2 in neurons in regulating acute stress responses, locomotion, and complex behaviours, and suggests that haploinsufficiency of YEATS2 may play a role in FAME4.</span></p></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"233 ","pages":"Article 102558"},"PeriodicalIF":6.7,"publicationDate":"2023-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138821059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pax3 induces target-specific reinnervation through axon collateral expression of PSA-NCAM","authors":"J. Sebastian Jara ,&nbsp;Hasan X. Avci ,&nbsp;Ioanna Kouremenou ,&nbsp;Mohamed Doulazmi ,&nbsp;Joelle Bakouche ,&nbsp;Caroline Dubacq ,&nbsp;Catherine Goyenvalle ,&nbsp;Jean Mariani ,&nbsp;Ann M. Lohof ,&nbsp;Rachel M. Sherrard","doi":"10.1016/j.pneurobio.2023.102560","DOIUrl":"10.1016/j.pneurobio.2023.102560","url":null,"abstract":"<div><p><span><span><span><span>Damaged or dysfunctional neural circuits can be replaced after a lesion by </span>axon sprouting and collateral growth from undamaged neurons. Unfortunately, these new connections are often disorganized and rarely produce clinical improvement. Here we investigate how to promote post-lesion axonal collateral growth, while retaining correct cellular targeting. In the mouse olivocerebellar path, brain-derived neurotrophic factor (BDNF) induces correctly-targeted post-lesion cerebellar </span>reinnervation by remaining intact inferior olivary axons (climbing fibers). In this study we identified cellular processes through which BDNF induces this repair. BDNF injection into the denervated </span>cerebellum<span> upregulates the transcription factor Pax3 in inferior olivary neurons and induces rapid climbing fiber sprouting. Pax3 in turn increases polysialic acid-neural cell adhesion molecule (PSA-NCAM) in the sprouting climbing fiber path, facilitating collateral outgrowth and pathfinding to reinnervate the correct targets, cerebellar Purkinje cells. BDNF-induced reinnervation can be reproduced by olivary </span></span><em>Pax3</em><span> overexpression, and abolished by olivary Pax3 knockdown, suggesting that Pax3 promotes axon growth </span><em>and</em><span> guidance through upregulating PSA-NCAM, probably on the axon’s growth cone<span>. These data indicate that restricting growth-promotion to potential reinnervating afferent neurons, as opposed to stimulating the whole circuit or the injury site, allows axon growth and appropriate guidance, thus accurately rebuilding a neural circuit.</span></span></p></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"232 ","pages":"Article 102560"},"PeriodicalIF":6.7,"publicationDate":"2023-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138580943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New Strategy of Micronutrients Combined with Dietary and Lifestyle Adjustment for Alzheimer’s Disease Therapy and Partial Restoration","authors":"Jin-Tao Li, Guanghui Xiu, Yueqin Zeng","doi":"10.60124/j.pneuro.2023.30.02","DOIUrl":"https://doi.org/10.60124/j.pneuro.2023.30.02","url":null,"abstract":"Alzheimer’s disease (AD), known as one of the most common cause of dementia, could lead to memory loss, difficulty with thinking and behavioral changes. To date, AD has been continuously regarded as an incurative disease of the aged and therefore as a big challenge for clinical neurology both in the therapy and prevention, which brings about heavy burden to not only the patients and their family, but also the society. In this review, it has been proposed a new strategy that would be synthetically implemented for the prevention and even partial restoration of AD clinically, in which multiple micronutrients, combined with diet and lifestyle adjustment, were used for AD patients and people who already had the pro-phase symptoms. Based on these notions, evidence and beneficial methods are put forward. It is promising to install a better and more efficacious AD administrative system, with aim to reduce the incidence rate and elevate the life quality of AD patients in a sooner future.","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"45 9","pages":""},"PeriodicalIF":6.7,"publicationDate":"2023-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139010357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRPM2 as a conserved gatekeeper determines the vulnerability of DA neurons by mediating ROS sensing and calcium dyshomeostasis","authors":"Peiwu Ye ,&nbsp;Qiuyuan Fang ,&nbsp;Xupang Hu ,&nbsp;Wenjuan Zou ,&nbsp;Miaodan Huang ,&nbsp;Minjing Ke ,&nbsp;Yunhao Li ,&nbsp;Min Liu ,&nbsp;Xiaobo Cai ,&nbsp;Congyi Zhang ,&nbsp;Ning Hua ,&nbsp;Umar Al-Sheikh ,&nbsp;Xingyu Liu ,&nbsp;Peilin Yu ,&nbsp;Peiran Jiang ,&nbsp;Ping-Yue Pan ,&nbsp;Jianhong Luo ,&nbsp;Lin-Hua Jiang ,&nbsp;Suhong Xu ,&nbsp;Evandro F. Fang ,&nbsp;Wei Yang","doi":"10.1016/j.pneurobio.2023.102530","DOIUrl":"10.1016/j.pneurobio.2023.102530","url":null,"abstract":"<div><p>Different dopaminergic (DA) neuronal subgroups exhibit distinct vulnerability to stress, while the underlying mechanisms are elusive. Here we report that the transient receptor potential melastatin 2 (TRPM2) channel is preferentially expressed in vulnerable DA neuronal subgroups, which correlates positively with aging in Parkinson’s Disease (PD) patients. Overexpression of human TRPM2 in the DA neurons of <em>C. elegans</em> resulted in selective death of ADE but not CEP neurons in aged worms. Mechanistically, TRPM2 activation mediates FZO-1/CED-9-dependent mitochondrial hyperfusion and mitochondrial permeability transition (MPT), leading to ADE death. In mice, TRPM2 knockout reduced vulnerable substantia nigra pars compacta (SNc) DA neuronal death induced by stress. Moreover, the TRPM2-mediated vulnerable DA neuronal death pathway is conserved from <em>C. elegans</em> to toxin-treated mice model and PD patient iPSC-derived DA neurons. The vulnerable SNc DA neuronal loss is the major symptom and cause of PD, and therefore the TRPM2-mediated pathway serves as a promising therapeutic target against PD.</p></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"231 ","pages":"Article 102530"},"PeriodicalIF":6.7,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301008223001314/pdfft?md5=20657e76f0d39d5523feb4f1d1f5c4f8&pid=1-s2.0-S0301008223001314-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41142044","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}