Pub Date : 2024-11-12DOI: 10.1016/j.nbd.2024.106733
Min Jeong Ku , Choong Yeon Kim , Jong Woo Park , Seohyeon Lee , Eun Young Jeong , Jae-Woong Jeong , Wha Young Kim , Jeong-Hoon Kim
Behavioral sensitization is defined as the heightened and persistent behavioral response to repeated drug exposure as a manifestation of drug craving. Psychomotor stimulants such as cocaine can induce strong behavioral sensitization. In this study, we explored the effects of optogenetic stimulation of the prelimbic (PL) to the nucleus accumbnes (NAc) core on the expression of cocaine-induced behavioral sensitization. Using wireless optogenetics, we selectively stimulated the PL-NAc core circuit, and assessed the effects of this treatment on cocaine-induced locomotor activity and accompanying changes in neuronal activation and dendritic spine density. Our findings revealed that optogenetic stimulation of the PL-NAc core circuit effectively suppressed the cocaine-induced locomotor sensitization, accompanied by a reduction in c-Fos expression within the NAc core. Moreover, optogenetic stimulation led to reduction in dendritic spine density, particularly thin and mushroom spine densities, in the NAc core. This study demonstrates that cocaine-induced locomotor sensitization can be regulated by optogenetic stimulation of the PL-NAc core circuit, providing insights into the crucial role of this circuit in psychomotor stimulant addiction.
{"title":"Wireless optogenetic stimulation on the prelimbic to the nucleus accumbens core circuit attenuates cocaine-induced behavioral sensitization","authors":"Min Jeong Ku , Choong Yeon Kim , Jong Woo Park , Seohyeon Lee , Eun Young Jeong , Jae-Woong Jeong , Wha Young Kim , Jeong-Hoon Kim","doi":"10.1016/j.nbd.2024.106733","DOIUrl":"10.1016/j.nbd.2024.106733","url":null,"abstract":"<div><div>Behavioral sensitization is defined as the heightened and persistent behavioral response to repeated drug exposure as a manifestation of drug craving. Psychomotor stimulants such as cocaine can induce strong behavioral sensitization. In this study, we explored the effects of optogenetic stimulation of the prelimbic (PL) to the nucleus accumbnes (NAc) core on the expression of cocaine-induced behavioral sensitization. Using wireless optogenetics, we selectively stimulated the PL-NAc core circuit, and assessed the effects of this treatment on cocaine-induced locomotor activity and accompanying changes in neuronal activation and dendritic spine density. Our findings revealed that optogenetic stimulation of the PL-NAc core circuit effectively suppressed the cocaine-induced locomotor sensitization, accompanied by a reduction in c-Fos expression within the NAc core. Moreover, optogenetic stimulation led to reduction in dendritic spine density, particularly thin and mushroom spine densities, in the NAc core. This study demonstrates that cocaine-induced locomotor sensitization can be regulated by optogenetic stimulation of the PL-NAc core circuit, providing insights into the crucial role of this circuit in psychomotor stimulant addiction.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"203 ","pages":"Article 106733"},"PeriodicalIF":5.1,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624579","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 : 2024-11-12DOI: 10.1016/j.nbd.2024.106734
Martina Cuccarelli , Alessandro Zampogna , Antonio Suppa
Malignant syndromes represent a group of medical conditions characterized by a rapid evolution of clinical manifestations, potentially leading to life-threatening complications if left untreated. These syndromes pose significant challenges for diagnosis and management, as they can lead to multisystem organ failure and death. Despite distinct features and origins, these syndromes share similar clinical presentation, pathophysiology, and the imperative for urgent medical intervention. While distinct mechanisms may initially trigger the different malignant syndromes, a final common pathway leading to similar signs and symptoms involves various neurotransmitter systems, including dopaminergic, serotonergic, GABAergic, glycinergic, and glutamatergic pathways. This narrative review examines the clinical presentations and potential causes of malignant syndromes, both highlighting shared pathophysiological mechanisms and emphasizing the critical importance of early recognition and intervention to mitigate potentially fatal outcomes. Although clinically heterogeneous, with variable motor and non-motor manifestations, most malignant syndromes share acute and rapid disruptions in physiological functions, including body temperature regulation, metabolism, control of the autonomic system and maintenance of consciousness. The potential for severe morbidity and mortality associated with these syndromes emphasizes the critical need for understanding their clinical characteristics, underlying mechanisms, and appropriate management strategies.
{"title":"The broad spectrum of malignant syndromes","authors":"Martina Cuccarelli , Alessandro Zampogna , Antonio Suppa","doi":"10.1016/j.nbd.2024.106734","DOIUrl":"10.1016/j.nbd.2024.106734","url":null,"abstract":"<div><div>Malignant syndromes represent a group of medical conditions characterized by a rapid evolution of clinical manifestations, potentially leading to life-threatening complications if left untreated. These syndromes pose significant challenges for diagnosis and management, as they can lead to multisystem organ failure and death. Despite distinct features and origins, these syndromes share similar clinical presentation, pathophysiology, and the imperative for urgent medical intervention. While distinct mechanisms may initially trigger the different malignant syndromes, a final common pathway leading to similar signs and symptoms involves various neurotransmitter systems, including dopaminergic, serotonergic, GABAergic, glycinergic, and glutamatergic pathways. This narrative review examines the clinical presentations and potential causes of malignant syndromes, both highlighting shared pathophysiological mechanisms and emphasizing the critical importance of early recognition and intervention to mitigate potentially fatal outcomes. Although clinically heterogeneous, with variable motor and non-motor manifestations, most malignant syndromes share acute and rapid disruptions in physiological functions, including body temperature regulation, metabolism, control of the autonomic system and maintenance of consciousness. The potential for severe morbidity and mortality associated with these syndromes emphasizes the critical need for understanding their clinical characteristics, underlying mechanisms, and appropriate management strategies.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"203 ","pages":"Article 106734"},"PeriodicalIF":5.1,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624577","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 : 2024-11-12DOI: 10.1016/j.nbd.2024.106732
Tadros A. Hana , Veronika G. Mousa , Alice Lin , Rawan N. Haj-Hussein , Andrew H. Michael , Madona N. Aziz , Sevinch U. Kamaridinova , Sabita Basnet , Kiel G. Ormerod
Huntington's Disease (HD) is a neurodegenerative disorder, part of the nine identified inherited polyglutamine (polyQ) diseases. Most commonly, HD pathophysiology manifests in middle-aged adults with symptoms including progressive loss of motor control, cognitive decline, and psychiatric disturbances. Associated with the pathophysiology of HD is the formation of insoluble fragments of the huntingtin protein (htt) that tend to aggregate in the nucleus and cytoplasm of neurons. To track both the intracellular progression of the aggregation phenotype as well as the physiological deficits associated with mutant htt, two constructs of human HTT were expressed in the Drosophila melanogaster nervous system with varying polyQ lengths, non-pathogenic-htt (NP-htt) and pathogenic-htt (P-htt), with an N-terminal RFP tag for in vivo visualization. P-htt aggregates accumulate in the ventral nerve cord cell bodies as early as 24 h post hatching and significant aggregates form in the segmental nerve branches at 48 h post hatching. Organelle trafficking up- and downstream of aggregates formed in motor neurons showed severe deficits in trafficking dynamics. To explore putative downstream deficits of htt aggregation, ultrastructural changes of presynaptic motor neurons and muscles were assessed, but no significant effects were observed. However, the force and kinetics of muscle contractions were severely affected in P-htt animals, reminiscent of human chorea. Reduced muscle force production translated to altered locomotory behavior. A novel HD aggregation model was established to track htt aggregation throughout adulthood in the wing, showing similar aggregation patterns with larvae. Expressing P-htt in the adult nervous system resulted in significantly reduced lifespan, which could be partially rescued by feeding flies the mTOR inhibitor rapamycin. These findings advance our understanding of htt aggregate progression as well the downstream physiological impacts on the nervous system and peripheral tissues.
亨廷顿舞蹈症（Huntington's Disease，HD）是一种神经退行性疾病，属于九种已确定的遗传性多聚谷氨酰胺（polyQ）疾病之一。大多数情况下，HD 的病理生理学表现为中年人的症状，包括进行性运动控制能力丧失、认知能力下降和精神障碍。与 HD 病理生理学相关的是亨廷蛋白（htt）不溶性片段的形成，这些片段往往聚集在神经元的细胞核和细胞质中。为了追踪细胞内聚集表型的进展以及与突变体 htt 相关的生理缺陷，我们在黑腹果蝇神经系统中表达了两种具有不同 polyQ 长度的人类 HTT 构建物：非致病性-htt（NP-htt）和致病性-htt（P-htt），其 N 端 RFP 标记用于体内可视化。P-htt聚集体早在孵化后24小时就在腹侧神经索细胞体中聚集，孵化后48小时在节段神经分支中形成大量聚集体。运动神经元中形成的聚集体上下游的细胞器贩运显示出严重的贩运动力学缺陷。为了探索 htt 聚集可能造成的下游缺陷，对突触前运动神经元和肌肉的超微结构变化进行了评估，但未观察到显著影响。然而，P-htt 动物肌肉收缩的力量和动力学受到严重影响，这让人联想到人类的舞蹈症。肌肉收缩力的降低导致了运动行为的改变。我们建立了一个新的HD聚集模型，以追踪整个成年期翅膀中htt的聚集情况，该模型显示出与幼虫相似的聚集模式。在成体神经系统中表达P-htt会导致寿命显著缩短，而给苍蝇喂食mTOR抑制剂雷帕霉素可以部分缓解这种情况。这些发现加深了我们对htt聚集进展以及对神经系统和外周组织的下游生理影响的理解。
{"title":"Developmental and physiological impacts of pathogenic human huntingtin protein in the nervous system","authors":"Tadros A. Hana , Veronika G. Mousa , Alice Lin , Rawan N. Haj-Hussein , Andrew H. Michael , Madona N. Aziz , Sevinch U. Kamaridinova , Sabita Basnet , Kiel G. Ormerod","doi":"10.1016/j.nbd.2024.106732","DOIUrl":"10.1016/j.nbd.2024.106732","url":null,"abstract":"<div><div>Huntington's Disease (HD) is a neurodegenerative disorder, part of the nine identified inherited polyglutamine (polyQ) diseases. Most commonly, HD pathophysiology manifests in middle-aged adults with symptoms including progressive loss of motor control, cognitive decline, and psychiatric disturbances. Associated with the pathophysiology of HD is the formation of insoluble fragments of the huntingtin protein (htt) that tend to aggregate in the nucleus and cytoplasm of neurons. To track both the intracellular progression of the aggregation phenotype as well as the physiological deficits associated with mutant htt, two constructs of human HTT were expressed in the <em>Drosophila melanogaster</em> nervous system with varying polyQ lengths, non-pathogenic-htt (NP-htt) and pathogenic-htt (P-htt), with an N-terminal RFP tag for <em>in vivo</em> visualization. P-htt aggregates accumulate in the ventral nerve cord cell bodies as early as 24 h post hatching and significant aggregates form in the segmental nerve branches at 48 h post hatching. Organelle trafficking up- and downstream of aggregates formed in motor neurons showed severe deficits in trafficking dynamics. To explore putative downstream deficits of htt aggregation, ultrastructural changes of presynaptic motor neurons and muscles were assessed, but no significant effects were observed. However, the force and kinetics of muscle contractions were severely affected in P-htt animals, reminiscent of human chorea. Reduced muscle force production translated to altered locomotory behavior. A novel HD aggregation model was established to track htt aggregation throughout adulthood in the wing, showing similar aggregation patterns with larvae. Expressing P-htt in the adult nervous system resulted in significantly reduced lifespan, which could be partially rescued by feeding flies the mTOR inhibitor rapamycin. These findings advance our understanding of htt aggregate progression as well the downstream physiological impacts on the nervous system and peripheral tissues.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"203 ","pages":"Article 106732"},"PeriodicalIF":5.1,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624570","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 : 2024-11-12DOI: 10.1016/j.nbd.2024.106725
Shin Ji Oh , Hyeongseop Kim , Sang Eon Park , Jeong Hee Kim , Yong Jun Kim , Suk-joo Choi , Soo-young Oh , Hong Bae Jeon , Jong Wook Chang
Charcot-Marie-Tooth disease type 1A (CMT1A) is a demyelinating disease caused by PMP22 duplication and an exceedingly rare hereditary peripheral neuropathy, with an incidence of 1 in 2500. Currently, no cure exists for CMT1A; however, various therapeutic approaches are under development. Considering the known therapeutic effects of mesenchymal stem cells (MSCs) and the relation of blood sugar levels with nerve damage in CMT, this study aimed to confirm the therapeutic effects of MSCs and insulin on CMT, using both in-vitro and in-vivo models. CMT1A in-vitro models were exposed to Wharton's jelly-derived MSCs (WJ-MSCs) or insulin, and the resulting proliferation changes were measured. CMT1A mice were treated with WJ-MSCs or insulin, and their phenotypic changes were observed. We observed improvements in myelination of Schwann cells in vitro and motor function in vivo. Insulin also showed therapeutic efficacy by promoting Schwann cell proliferation. Furthermore, combination therapy using insulin and WJ-MSCs was more effective than WJ-MSCs or insulin alone. Insulin promoted the proliferation of Schwann cells and WJ-MSCs through activation of the ATK and PI3K-MAPK signaling pathways. Overall, this study is the first to confirm the therapeutic efficacy of WJ-MSCs and insulin in CMT1A, and their synergistic effect without causing insulin resistance.
{"title":"Synergistic effect of Wharton's jelly-derived mesenchymal stem cells and insulin on Schwann cell proliferation in Charcot-Marie-Tooth disease type 1A treatment","authors":"Shin Ji Oh , Hyeongseop Kim , Sang Eon Park , Jeong Hee Kim , Yong Jun Kim , Suk-joo Choi , Soo-young Oh , Hong Bae Jeon , Jong Wook Chang","doi":"10.1016/j.nbd.2024.106725","DOIUrl":"10.1016/j.nbd.2024.106725","url":null,"abstract":"<div><div>Charcot-Marie-Tooth disease type 1A (CMT1A) is a demyelinating disease caused by <em>PMP22</em> duplication and an exceedingly rare hereditary peripheral neuropathy, with an incidence of 1 in 2500. Currently, no cure exists for CMT1A; however, various therapeutic approaches are under development. Considering the known therapeutic effects of mesenchymal stem cells (MSCs) and the relation of blood sugar levels with nerve damage in CMT, this study aimed to confirm the therapeutic effects of MSCs and insulin on CMT, using both <em>in-vitro</em> and <em>in-vivo</em> models. CMT1A <em>in-vitro</em> models were exposed to Wharton's jelly-derived MSCs (WJ-MSCs) or insulin, and the resulting proliferation changes were measured. CMT1A mice were treated with WJ-MSCs or insulin, and their phenotypic changes were observed. We observed improvements in myelination of Schwann cells <em>in vitro</em> and motor function <em>in vivo</em>. Insulin also showed therapeutic efficacy by promoting Schwann cell proliferation. Furthermore, combination therapy using insulin and WJ-MSCs was more effective than WJ-MSCs or insulin alone. Insulin promoted the proliferation of Schwann cells and WJ-MSCs through activation of the ATK and PI3K-MAPK signaling pathways. Overall, this study is the first to confirm the therapeutic efficacy of WJ-MSCs and insulin in CMT1A, and their synergistic effect without causing insulin resistance.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"203 ","pages":"Article 106725"},"PeriodicalIF":5.1,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624574","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 : 2024-11-10DOI: 10.1016/j.nbd.2024.106731
J. Lyu , M.L. MacDonald , S. Ruiz , S. Chou , J. Gilardi , S.C. Buchwald , M.J. Grubisha , R.A. Sweet
Microtubule-associated protein 2 (MAP2) is a crucial regulator of dendritic structure and neuronal function, orchestrating diverse protein interactions within the microtubule network. We have shown MAP2 is hyperphosphorylated at serine 1782 (S1782) in schizophrenia and phosphomimetic mutation of S1782 in mice (MAP2S1782E) is sufficient to impair dendritic architecture. We sought to determine how this hyperphosphorylation affects the MAP2 interactome to provide insights into the disorder's mechanisms. We investigated the MAP2 interactome using co-immunoprecipitation and mass spectrometry in MAP2S1782E and MAP2WT mice. We found that S1782E MAP2 led to a substantial disruption of protein-protein interactions relative to WT MAP2. Reduced interactions with PDZ domain-containing proteins, calmodulin-binding proteins, ribosome proteins, and kinesin proteins may all contribute to dendritic impairments induced by S1782E, and may be linked to schizophrenia pathogenesis. Interestingly, novel gain-of-function interactions with PPM1L and KLHL8 nominated these as regulators of phosphoS1782 MAP2 abundance and potential therapeutic targets in schizophrenia.
{"title":"Deciphering the alteration of MAP2 interactome caused by a schizophrenia-associated phosphorylation","authors":"J. Lyu , M.L. MacDonald , S. Ruiz , S. Chou , J. Gilardi , S.C. Buchwald , M.J. Grubisha , R.A. Sweet","doi":"10.1016/j.nbd.2024.106731","DOIUrl":"10.1016/j.nbd.2024.106731","url":null,"abstract":"<div><div>Microtubule-associated protein 2 (MAP2) is a crucial regulator of dendritic structure and neuronal function, orchestrating diverse protein interactions within the microtubule network. We have shown MAP2 is hyperphosphorylated at serine 1782 (S1782) in schizophrenia and phosphomimetic mutation of S1782 in mice (MAP2<sup>S1782E</sup>) is sufficient to impair dendritic architecture. We sought to determine how this hyperphosphorylation affects the MAP2 interactome to provide insights into the disorder's mechanisms. We investigated the MAP2 interactome using co-immunoprecipitation and mass spectrometry in MAP2<sup>S1782E</sup> and MAP2<sup>WT</sup> mice. We found that S1782E MAP2 led to a substantial disruption of protein-protein interactions relative to WT MAP2. Reduced interactions with PDZ domain-containing proteins, calmodulin-binding proteins, ribosome proteins, and kinesin proteins may all contribute to dendritic impairments induced by S1782E, and may be linked to schizophrenia pathogenesis. Interestingly, novel gain-of-function interactions with PPM1L and KLHL8 nominated these as regulators of phosphoS1782 MAP2 abundance and potential therapeutic targets in schizophrenia.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"203 ","pages":"Article 106731"},"PeriodicalIF":5.1,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624568","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 : 2024-11-08DOI: 10.1016/j.nbd.2024.106730
Merel M. van der Thiel , Nienke van de Sande , Anouk Meeusen , Gerhard S. Drenthen , Alida A. Postma , Rudy M.M.A. Nuijts , Noa van der Knaap , Inez H.G.B. Ramakers , Carroll A.B. Webers , Walter H. Backes , Marlies Gijs , Jacobus F.A. Jansen
Impaired cerebral waste clearance (i.e., glymphatics) is evident in aging and neurodegenerative disorders, such as Alzheimer's disease, where an impaired waste clearance system could be related to the accumulation of pathological proteins (e.g., tau). One marker of impaired cerebral clearance is the abundance of enlarged perivascular spaces (PVS). Preclinical studies propose a similar clearance system in the eye, driven by intraocular pressure (IOP). This cross-sectional pilot study explores the link between ocular and cerebral waste clearance by examining the association between MRI-visible PVS, tear fluid total-tau, and IOP.
Thirty cognitively healthy participants, all aged over 55 years, underwent 7 Tesla MRI, with PVS visually rated in the centrum semiovale (CSO) and basal ganglia. Tear fluid was collected using paper Schirmer's strips and analyzed for total-tau using enzyme-linked immunosorbent assay. IOP was measured using non-contact tonometry. Partial Spearman's correlation coefficients of eye and brain markers were calculated, adjusted for age, sex, tear fluid-wetting length, and hemispheric region of interest volume.
Higher CSO PVS scores in the left and right hemisphere were associated with higher levels of tear fluid total-tau. Higher CSO PVS scores in both hemispheres were related to lower ipsilateral IOP. The exploratory results suggest that higher tear fluid total-tau and a reduced driving force of ocular waste clearance are connected to impaired cerebral waste clearance in cognitive healthy individuals. This study connects the potential ocular glymphatic system to the cerebral waste clearance system. Clarifying waste clearance biology and validating eye biomarkers for cerebral waste clearance could provide treatment targets and diagnostic opportunities for neurological diseases.
在衰老和神经退行性疾病（如阿尔茨海默病）中，大脑废物清除（即glymphatics）功能受损是显而易见的，废物清除系统受损可能与病理蛋白（如tau）的积累有关。脑清除功能受损的一个标志是血管周围空隙（PVS）大量扩大。临床前研究提出，眼内压（IOP）也会驱动类似的清除系统。这项横断面试验性研究通过检查核磁共振成像可见血管周围间隙、泪液总陶和眼压之间的关联，探索眼部和大脑废物清除之间的联系。30 名认知健康的参与者（年龄均超过 55 岁）接受了 7 T 磁共振成像检查，并对半脑中心（CSO）和基底节的 PVS 进行了目测评级。使用纸质施尔默试纸收集泪液，并使用酶联免疫吸附法分析总 tau。使用非接触式眼压计测量眼压。计算了眼睛和大脑标记物的部分斯皮尔曼相关系数，并对年龄、性别、泪液湿润长度和半球感兴趣区体积进行了调整。左半球和右半球较高的 CSO PVS 分数与较高的泪液总 tau 水平相关。两个半球的 CSO PVS 分数越高，同侧眼压越低。探索性结果表明，在认知健康的个体中，较高的泪液总tau和眼部废物清除驱动力的降低与大脑废物清除受损有关。这项研究将潜在的眼部甘液系统与大脑废物清除联系起来。阐明废物清除生物学原理并验证眼部生物标记物对大脑废物清除的作用，可为神经系统疾病提供治疗目标和诊断机会。
{"title":"Linking human cerebral and ocular waste clearance: Insights from tear fluid and ultra-high field MRI","authors":"Merel M. van der Thiel , Nienke van de Sande , Anouk Meeusen , Gerhard S. Drenthen , Alida A. Postma , Rudy M.M.A. Nuijts , Noa van der Knaap , Inez H.G.B. Ramakers , Carroll A.B. Webers , Walter H. Backes , Marlies Gijs , Jacobus F.A. Jansen","doi":"10.1016/j.nbd.2024.106730","DOIUrl":"10.1016/j.nbd.2024.106730","url":null,"abstract":"<div><div>Impaired cerebral waste clearance (i.e., glymphatics) is evident in aging and neurodegenerative disorders, such as Alzheimer's disease, where an impaired waste clearance system could be related to the accumulation of pathological proteins (e.g., tau). One marker of impaired cerebral clearance is the abundance of enlarged perivascular spaces (PVS). Preclinical studies propose a similar clearance system in the eye, driven by intraocular pressure (IOP). This cross-sectional pilot study explores the link between ocular and cerebral waste clearance by examining the association between MRI-visible PVS, tear fluid total-tau, and IOP.</div><div>Thirty cognitively healthy participants, all aged over 55 years, underwent 7 Tesla MRI, with PVS visually rated in the centrum semiovale (CSO) and basal ganglia. Tear fluid was collected using paper Schirmer's strips and analyzed for total-tau using enzyme-linked immunosorbent assay. IOP was measured using non-contact tonometry. Partial Spearman's correlation coefficients of eye and brain markers were calculated, adjusted for age, sex, tear fluid-wetting length, and hemispheric region of interest volume.</div><div>Higher CSO PVS scores in the left and right hemisphere were associated with higher levels of tear fluid total-tau. Higher CSO PVS scores in both hemispheres were related to lower ipsilateral IOP. The exploratory results suggest that higher tear fluid total-tau and a reduced driving force of ocular waste clearance are connected to impaired cerebral waste clearance in cognitive healthy individuals. This study connects the potential ocular glymphatic system to the cerebral waste clearance system. Clarifying waste clearance biology and validating eye biomarkers for cerebral waste clearance could provide treatment targets and diagnostic opportunities for neurological diseases.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"203 ","pages":"Article 106730"},"PeriodicalIF":5.1,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624572","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 : 2024-11-01DOI: 10.1016/j.nbd.2024.106728
Josefine Fussing Tengberg , Francesco Russo , Tau Benned-Jensen , Jacob Nielsen
Abstract
Activating mutations in Leucine Rich Repeat Kinase 2 (LRRK2) are among the most common genetic causes of Parkinson's disease (PD). The mechanistic path from LRRK2 mutations to PD is not established, but several lines of data suggest that LRRK2 modulation of lysosomal function is involved. It has previously been shown that LRRK2 is recruited to lysosomes upon lysosomal damage leading to increased phosphorylation of its RAB GTPase substrates in macrophage-derived RAW 264.7 cells. Here, we find that LRRK2 kinase inhibition reduces cell death induced by the lysosomotropic compound LLOMe in RAW 264.7 cells showing that lysosomal damage and LRRK2 functionally interacts in both directions: lysosomal damage can lead to activation of LRRK2 signaling and LRRK2 inhibition can attenuate LLOMe-induced cell death. The effect is lysosome specific, as only lysosomal stressors and not a variety of other cell death inducers could be modulated by LRRK2 kinase inhibition. We show with timing and Lysotracker experiments that LRRK2 inhibition does not affect the immediate lysosomal permeabilization induced by LLOMe, but rather modulates the subsequent cellular response to lysosomal damage. siRNA-mediated knockdown of LRRK2 and its main substrates, the RAB GTPases, showed that LRRK2 and RAB8A knockdown could attenuate LLOMe-induced cell death, but not other RAB GTPases tested. An RNA sequencing study was done to identify downstream pathways modulated by LLOMe and LRRK2 inhibition. The most striking finding was that almost all cholesterol biosynthesis genes were strongly downregulated by LLOMe and upregulated with LRRK2 inhibition in combination with LLOMe treatment. To explore the functional relevance of the transcriptional changes, we pretreated cells with the NPC1 inhibitor U18666A that can lead to accumulation of lysosomal cholesterol. U18666A-treated cells were less sensitive to LLOMe-induced cell death, but the attenuation of cell death by LRRK2 inhibition was strongly reduced suggesting that LRRK2 inhibition and lysosomal cholesterol reduces cell death by overlapping mechanisms. Thus, our data demonstrates a LRRK2- and RAB8A-mediated attenuation of RAW 264.7 cell death induced by lysosomal damage that is modulated by lysosomal cholesterol.
{"title":"LRRK2 and RAB8A regulate cell death after lysosomal damage in macrophages through cholesterol-related pathways","authors":"Josefine Fussing Tengberg , Francesco Russo , Tau Benned-Jensen , Jacob Nielsen","doi":"10.1016/j.nbd.2024.106728","DOIUrl":"10.1016/j.nbd.2024.106728","url":null,"abstract":"<div><div>Abstract</div><div>Activating mutations in Leucine Rich Repeat Kinase 2 (LRRK2) are among the most common genetic causes of Parkinson's disease (PD). The mechanistic path from LRRK2 mutations to PD is not established, but several lines of data suggest that LRRK2 modulation of lysosomal function is involved. It has previously been shown that LRRK2 is recruited to lysosomes upon lysosomal damage leading to increased phosphorylation of its RAB GTPase substrates in macrophage-derived RAW 264.7 cells. Here, we find that LRRK2 kinase inhibition reduces cell death induced by the lysosomotropic compound LLOMe in RAW 264.7 cells showing that lysosomal damage and LRRK2 functionally interacts in both directions: lysosomal damage can lead to activation of LRRK2 signaling and LRRK2 inhibition can attenuate LLOMe-induced cell death. The effect is lysosome specific, as only lysosomal stressors and not a variety of other cell death inducers could be modulated by LRRK2 kinase inhibition. We show with timing and Lysotracker experiments that LRRK2 inhibition does not affect the immediate lysosomal permeabilization induced by LLOMe, but rather modulates the subsequent cellular response to lysosomal damage. siRNA-mediated knockdown of LRRK2 and its main substrates, the RAB GTPases, showed that LRRK2 and RAB8A knockdown could attenuate LLOMe-induced cell death, but not other RAB GTPases tested. An RNA sequencing study was done to identify downstream pathways modulated by LLOMe and LRRK2 inhibition. The most striking finding was that almost all cholesterol biosynthesis genes were strongly downregulated by LLOMe and upregulated with LRRK2 inhibition in combination with LLOMe treatment. To explore the functional relevance of the transcriptional changes, we pretreated cells with the NPC1 inhibitor U18666A that can lead to accumulation of lysosomal cholesterol. U18666A-treated cells were less sensitive to LLOMe-induced cell death, but the attenuation of cell death by LRRK2 inhibition was strongly reduced suggesting that LRRK2 inhibition and lysosomal cholesterol reduces cell death by overlapping mechanisms. Thus, our data demonstrates a LRRK2- and RAB8A-mediated attenuation of RAW 264.7 cell death induced by lysosomal damage that is modulated by lysosomal cholesterol.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"202 ","pages":"Article 106728"},"PeriodicalIF":5.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624599","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 : 2024-11-01DOI: 10.1016/j.nbd.2024.106716
Zhenyu Cheng , Linfeng Yang , Jing Li , Yiwen Chen , Pengcheng Liang , Yuanyuan Wang , Na Wang , Xinyue Zhang , Yian Gao , Chaofan Sui , Meng Li , Changhu Liang , Lingfei Guo
Although the amygdala is associated with cognitive impairment resulting from cerebral small vessel disease, the relationship between alterations in amygdala structure and cerebral small vessel disease (CSVD) remains controversial. Given that the amygdala comprises several subregions, detecting subtle regional changes through total amygdala volume measurement is challenging. This study aimed to identify the patterns of amygdala subregion atrophy in cerebral small vessel disease patients and their relationship with cognitive impairment. A total of 114 participants diagnosed with cerebral small vessel disease and 129 healthy participants, aged 40 to 70, underwent 3 T magnetic resonance imaging scans. The amygdala subregions were automatically segmented using FreeSurfer. In the Propensity Score Matching (PSM)-matched cohort, Lasso regression was employed to identify subregions associated with cerebral small vessel disease, and restricted cubic splines (RCS) were used to explore their nonlinear relationship with cognitive abilities. Subsequently, multivariate linear regression models were used to investigate the impact of amygdala subregion volumes on various cognitive abilities. Compared to healthy controls (HC), the volume of the left cortical nucleus was significantly reduced in cerebral small vessel disease patients. The volume of the left cortical nucleus was significantly negatively correlated with cerebral small vessel disease progression, and atrophy in this region was also identified as an independent risk factor for decreased cognitive control and processing ability. Our findings suggest that patients with cerebral small vessel disease exhibit atrophy in specific amygdala subregions compared to healthy controls, which correlates with poorer cognitive control and processing abilities. These insights may advance our understanding of the pathogenesis of cerebral small vessel disease.
{"title":"Cognitive impairment and amygdala subregion volumes in elderly with cerebral small vessel disease: A large prospective cohort study","authors":"Zhenyu Cheng , Linfeng Yang , Jing Li , Yiwen Chen , Pengcheng Liang , Yuanyuan Wang , Na Wang , Xinyue Zhang , Yian Gao , Chaofan Sui , Meng Li , Changhu Liang , Lingfei Guo","doi":"10.1016/j.nbd.2024.106716","DOIUrl":"10.1016/j.nbd.2024.106716","url":null,"abstract":"<div><div>Although the amygdala is associated with cognitive impairment resulting from cerebral small vessel disease, the relationship between alterations in amygdala structure and cerebral small vessel disease (CSVD) remains controversial. Given that the amygdala comprises several subregions, detecting subtle regional changes through total amygdala volume measurement is challenging. This study aimed to identify the patterns of amygdala subregion atrophy in cerebral small vessel disease patients and their relationship with cognitive impairment. A total of 114 participants diagnosed with cerebral small vessel disease and 129 healthy participants, aged 40 to 70, underwent 3 T magnetic resonance imaging scans. The amygdala subregions were automatically segmented using FreeSurfer. In the Propensity Score Matching (PSM)-matched cohort, Lasso regression was employed to identify subregions associated with cerebral small vessel disease, and restricted cubic splines (RCS) were used to explore their nonlinear relationship with cognitive abilities. Subsequently, multivariate linear regression models were used to investigate the impact of amygdala subregion volumes on various cognitive abilities. Compared to healthy controls (HC), the volume of the left cortical nucleus was significantly reduced in cerebral small vessel disease patients. The volume of the left cortical nucleus was significantly negatively correlated with cerebral small vessel disease progression, and atrophy in this region was also identified as an independent risk factor for decreased cognitive control and processing ability. Our findings suggest that patients with cerebral small vessel disease exhibit atrophy in specific amygdala subregions compared to healthy controls, which correlates with poorer cognitive control and processing abilities. These insights may advance our understanding of the pathogenesis of cerebral small vessel disease.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"202 ","pages":"Article 106716"},"PeriodicalIF":5.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569323","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 : 2024-11-01DOI: 10.1016/j.nbd.2024.106720
Clémence Disdier , Amélie Soyer , Léa Broca-Brisson , Sébastien Goutal , Anne-Cécile Guyot , Nora Ziani , Louise Breuil , Alexandra Winkeler , Gaëlle Hugon , Thomas Joudinaud , Henri Bénech , Jean Armengaud , Matthew R. Skelton , Rania Harati , Rifat A. Hamoudi , Nicolas Tournier , Aloïse Mabondzo
Creatine transporter deficiency (CTD) is an inborn error of creatine (Cr) metabolism in which Cr is not properly distributed to the brain due to a mutation in the Cr transporter (CrT) SLC6A8 gene. CTD is associated with developmental delays and with neurological disability in children. Dodecyl creatine ester (DCE), as a Cr prodrug, is a promising drug to treat CTD after administration by the nasal route, taking advantage of the nose-to-brain pathway. In this study, the potential adaptive response to energy imbalance in glucose metabolism was investigated in CTD using both SLC6A8-deficient mice (CrT KO) and brain organoids derived from CTD patient cells. Longitudinal brain [18F]FDG PET imaging in CrT KO mice compared to wild-type mice demonstrated that CTD was associated with a significant loss and decline in brain glucose metabolism. In CrT KO mice, intranasal supplementation with DCE for a month significantly mitigated the decline in brain glucose metabolism compared to untreated (vehicle) animals. Mechanistic investigations in CrT KO mice and cerebral organoids derived from CTD patient cells suggest that intracellular trafficking of glucose transporter (Glut) may be altered by lack of activation of AMP-activated protein kinase (AMPK). Consistency between observations in the CrT KO mouse model and cerebral organoids derived from CTD patient cells supports the value of this new model for drug discovery and development. In addition, these results suggest that [18F]FDG PET imaging may offer a unique and minimally-invasive biomarker to monitor the impact of investigational treatment on CTD pathophysiology, with translational perspectives.
肌酸转运体缺乏症（CTD）是肌酸（Cr）代谢的一种先天性错误，由于肌酸转运体（CrT）SLC6A8 基因突变，Cr 无法正常分布到大脑。CTD 与儿童发育迟缓和神经系统残疾有关。十二烷基肌酸酯（DCE）作为一种Cr原药，通过鼻腔给药，利用鼻腔到大脑的通路，是治疗CTD的一种很有前景的药物。本研究利用SLC6A8缺陷小鼠（CrT KO）和从CTD患者细胞中提取的脑器官组织研究了CTD对葡萄糖代谢能量失衡的潜在适应性反应。与野生型小鼠相比，CrT KO小鼠的纵向脑[18F]FDG PET成像显示，CTD与脑葡萄糖代谢的显著丧失和下降有关。在 CrT KO 小鼠中，与未经处理（载体）的动物相比，连续一个月鼻内补充 DCE 可显著缓解脑糖代谢的下降。对 CrT KO 小鼠和 CTD 患者细胞衍生的脑器官组织的机理研究表明，葡萄糖转运体（Glut）的胞内转运可能因缺乏 AMP 激活蛋白激酶（AMPK）的激活而发生改变。在CrT KO小鼠模型和从CTD患者细胞中提取的脑器官组织中观察到的结果一致，这支持了这种新模型在药物发现和开发方面的价值。此外，这些结果表明，[18F]FDG PET 成像可提供一种独特的微创生物标记物，用于监测研究性治疗对 CTD 病理生理学的影响，并具有转化前景。
{"title":"Impaired brain glucose metabolism as a biomarker for evaluation of dodecyl creatine ester in creatine transporter deficiency: Insights from patient brain-derived organoids and in vivo [18F]FDG PET imaging in a mouse model","authors":"Clémence Disdier , Amélie Soyer , Léa Broca-Brisson , Sébastien Goutal , Anne-Cécile Guyot , Nora Ziani , Louise Breuil , Alexandra Winkeler , Gaëlle Hugon , Thomas Joudinaud , Henri Bénech , Jean Armengaud , Matthew R. Skelton , Rania Harati , Rifat A. Hamoudi , Nicolas Tournier , Aloïse Mabondzo","doi":"10.1016/j.nbd.2024.106720","DOIUrl":"10.1016/j.nbd.2024.106720","url":null,"abstract":"<div><div>Creatine transporter deficiency (CTD) is an inborn error of creatine (Cr) metabolism in which Cr is not properly distributed to the brain due to a mutation in the Cr transporter (CrT) <em>SLC6A8</em> gene. CTD is associated with developmental delays and with neurological disability in children. Dodecyl creatine ester (DCE), as a Cr prodrug, is a promising drug to treat CTD after administration by the nasal route, taking advantage of the nose-to-brain pathway. In this study, the potential adaptive response to energy imbalance in glucose metabolism was investigated in CTD using both <em>SLC6A8</em>-deficient mice (CrT KO) and brain organoids derived from CTD patient cells. Longitudinal brain [<sup>18</sup>F]FDG PET imaging in CrT KO mice compared to wild-type mice demonstrated that CTD was associated with a significant loss and decline in brain glucose metabolism. In CrT KO mice, intranasal supplementation with DCE for a month significantly mitigated the decline in brain glucose metabolism compared to untreated (vehicle) animals. Mechanistic investigations in CrT KO mice and cerebral organoids derived from CTD patient cells suggest that intracellular trafficking of glucose transporter (Glut) may be altered by lack of activation of AMP-activated protein kinase (AMPK). Consistency between observations in the CrT KO mouse model and cerebral organoids derived from CTD patient cells supports the value of this new model for drug discovery and development. In addition, these results suggest that [<sup>18</sup>F]FDG PET imaging may offer a unique and minimally-invasive biomarker to monitor the impact of investigational treatment on CTD pathophysiology, with translational perspectives.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"202 ","pages":"Article 106720"},"PeriodicalIF":5.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142560526","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 : 2024-11-01DOI: 10.1016/j.nbd.2024.106708
Juan M. Godoy-Corchuelo , Zeinab Ali , Jose M. Brito Armas , Aurea B. Martins-Bach , Irene García-Toledo , Luis C. Fernandez-Beltrán , Juan I. Lopez-Carbonero , Pablo Bascunana , Shoshana Spring , Irene Jimenez-Coca , Ramón A. Muñozde Bustillo Alfaro , Maria J. Sanchez-Barrena , Remya R. Nair , Brian J. Nieman , Jason P. Lerch , Karla L. Miller , Hande P. Ozdinler , Elizabeth M.C. Fisher , Thomas J. Cunningham , Abraham Acevedo-Arozena , Silvia Corrochano
{"title":"Corrigendum to “TDP-43-M323K causes abnormal brain development and progressive cognitive and motor deficits associated with mislocalised and increased levels of TDP-43” [Neurobiology of disease Volume 193, April 2024, 106437]","authors":"Juan M. Godoy-Corchuelo , Zeinab Ali , Jose M. Brito Armas , Aurea B. Martins-Bach , Irene García-Toledo , Luis C. Fernandez-Beltrán , Juan I. Lopez-Carbonero , Pablo Bascunana , Shoshana Spring , Irene Jimenez-Coca , Ramón A. Muñozde Bustillo Alfaro , Maria J. Sanchez-Barrena , Remya R. Nair , Brian J. Nieman , Jason P. Lerch , Karla L. Miller , Hande P. Ozdinler , Elizabeth M.C. Fisher , Thomas J. Cunningham , Abraham Acevedo-Arozena , Silvia Corrochano","doi":"10.1016/j.nbd.2024.106708","DOIUrl":"10.1016/j.nbd.2024.106708","url":null,"abstract":"","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"202 ","pages":"Article 106708"},"PeriodicalIF":5.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504771","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}
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