Neurobiology of Disease最新文献_第7页

Identifying disulfidptosis-related biomarkers in epilepsy based on integrated bioinformatics and experimental analyses 基于综合生物信息学和实验分析鉴定癫痫中与二硫中毒相关的生物标志物。

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2025-02-01 DOI: 10.1016/j.nbd.2025.106789

Sijun Li , Lanfeng Sun , Hongmi Huang , Xing Wei, Yuling Lu, Kai Qian, Yuan Wu

One of the underlying mechanisms of epilepsy (EP), a brain disease characterized by recurrent seizures, is considered to be cell death. Disulfidptosis, a proposed novel cell death mechanism, is thought to play a part in the pathogenesis of epilepsy, but the exact role is unclear. The gene expression omnibus series (GSE) 33000 and GSE63808 datasets were used to search for differentially expressed disulfidptosis-related molecules (DE-DRMs). A correlation between the DE-DRMs was discovered. Individuals with epilepsy were then used to investigate molecular clusters based on the expression of DE-DRMs. Following that, the best machine learning model which is validated by GSE143272 dataset and predictor molecules were identified. The correlation between predictive molecules and clinical traits was determined. Based on the in vitro and in vivo seizures models, experimental analyses were applied to verify the DE-DRMs expressions and the correlation between them. Nine molecules were identified as DE-DRMs: glycogen synthase 1 (GYS1), solute carrier family 3 member 2 (SLC3A2), solute carrier family 7 member 11 (SLC7A11), NADH:ubiquinone oxidoreductase core subunit S1 (NDUFS1), 3-oxoacyl-ACP synthase, mitochondrial (OXSM), leucine rich pentatricopeptide repeat containing (LRPPRC), NADH:ubiquinone oxidoreductase subunit A11 (NDUFA11), NUBP iron‑sulfur cluster assembly factor, mitochondrial (NUBPL), and NCK associated protein 1 (NCKAP1). NDUFS1 interacted with NDUFA11, NUBPL, and LRPPRC, while SLC3A2 interacted with SLC7A11. The optimal machine learning model was revealed to be the random forest (RF) model. G protein guanine nucleotide-binding protein alpha subunit q (GNAQ) was linked to sodium valproate resistance. The experimental analyses suggested an upregulated SLC7A11 expression, an increased number of formed SLC3A2 and SLC7A11 complexes, and a decreased number of formed NDUFS1 and NDUFA11 complexes. This study provides previously undocumented evidence of the relationship between disulfidptosis and EP. In addition to suggesting that SLC7A11 may be a specific DRM for EP, this research demonstrates the alterations in two disulfidptosis-related protein complexes: SLC7A11-SLC3A2 and NDUFS1-NDUFA11.

癫痫（EP）是一种以反复发作为特征的脑部疾病，其潜在机制之一被认为是细胞死亡。双曲下垂是一种新的细胞死亡机制，被认为在癫痫的发病机制中起作用，但确切的作用尚不清楚。使用基因表达综合系列（GSE） 33000和GSE63808数据集搜索差异表达的二硫中毒相关分子（DE-DRMs）。发现了de - drm之间的相关性。然后使用癫痫患者来研究基于DE-DRMs表达的分子簇。然后，通过GSE143272数据集和预测分子验证，确定了最佳机器学习模型。预测分子与临床特征之间的相关性被确定。基于离体和体内癫痫模型，通过实验分析验证DE-DRMs的表达及其相关性。9个分子被鉴定为DE-DRMs：糖原合成酶1 （GYS1）、溶质载体家族3成员2 （SLC3A2）、溶质载体家族7成员11 （SLC7A11）、NADH：泛醌氧化还原酶核心亚基S1 （NDUFS1）、3-氧酰基- acp合成酶、线粒体（OXSM）、富含亮氨酸的五肽重复序列（LRPPRC）、NADH：泛醌氧化还原酶亚基A11 （NDUFA11）、NUBP铁硫集群组装因子、线粒体（NUBPL）和NCK相关蛋白1 （NCKAP1）。NDUFS1与NDUFA11、NUBPL和LRPPRC相互作用，SLC3A2与SLC7A11相互作用。最优的机器学习模型是随机森林（RF）模型。G蛋白鸟嘌呤核苷酸结合蛋白α亚基q （GNAQ）与丙戊酸钠耐药有关。实验分析表明SLC7A11表达上调，SLC3A2和SLC7A11复合物的形成数量增加，NDUFS1和NDUFA11复合物的形成数量减少。这项研究提供了先前未记载的证据，证明了上睑下垂和EP之间的关系。除了提示SLC7A11可能是EP的特异性DRM外，本研究还证实了两种二硫分解相关蛋白复合物的改变：SLC7A11- slc3a2和NDUFS1-NDUFA11。

{"title":"Identifying disulfidptosis-related biomarkers in epilepsy based on integrated bioinformatics and experimental analyses","authors":"Sijun Li , Lanfeng Sun , Hongmi Huang , Xing Wei, Yuling Lu, Kai Qian, Yuan Wu","doi":"10.1016/j.nbd.2025.106789","DOIUrl":"10.1016/j.nbd.2025.106789","url":null,"abstract":"<div><div>One of the underlying mechanisms of epilepsy (EP), a brain disease characterized by recurrent seizures, is considered to be cell death. Disulfidptosis, a proposed novel cell death mechanism, is thought to play a part in the pathogenesis of epilepsy, but the exact role is unclear. The gene expression omnibus series (GSE) 33000 and GSE63808 datasets were used to search for differentially expressed disulfidptosis-related molecules (DE-DRMs). A correlation between the DE-DRMs was discovered. Individuals with epilepsy were then used to investigate molecular clusters based on the expression of DE-DRMs. Following that, the best machine learning model which is validated by GSE143272 dataset and predictor molecules were identified. The correlation between predictive molecules and clinical traits was determined. Based on the <em>in vitro</em> and <em>in vivo</em> seizures models, experimental analyses were applied to verify the DE-DRMs expressions and the correlation between them. Nine molecules were identified as DE-DRMs: glycogen synthase 1 (GYS1), solute carrier family 3 member 2 (SLC3A2), solute carrier family 7 member 11 (SLC7A11), NADH:ubiquinone oxidoreductase core subunit S1 (NDUFS1), 3-oxoacyl-ACP synthase, mitochondrial (OXSM), leucine rich pentatricopeptide repeat containing (LRPPRC), NADH:ubiquinone oxidoreductase subunit A11 (NDUFA11), NUBP iron‑sulfur cluster assembly factor, mitochondrial (NUBPL), and NCK associated protein 1 (NCKAP1). NDUFS1 interacted with NDUFA11, NUBPL, and LRPPRC, while SLC3A2 interacted with SLC7A11. The optimal machine learning model was revealed to be the random forest (RF) model. G protein guanine nucleotide-binding protein alpha subunit q (GNAQ) was linked to sodium valproate resistance. The experimental analyses suggested an upregulated SLC7A11 expression, an increased number of formed SLC3A2 and SLC7A11 complexes, and a decreased number of formed NDUFS1 and NDUFA11 complexes. This study provides previously undocumented evidence of the relationship between disulfidptosis and EP. In addition to suggesting that SLC7A11 may be a specific DRM for EP, this research demonstrates the alterations in two disulfidptosis-related protein complexes: SLC7A11-SLC3A2 and NDUFS1-NDUFA11.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"205 ","pages":"Article 106789"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142979353","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}

引用次数: 0

Pleiotrophin deletion prevents high-fat diet-induced cognitive impairment, glial responses, and alterations of the perineuronal nets in the hippocampus 多营养蛋白缺失可防止高脂肪饮食引起的认知障碍、神经胶质反应和海马神经元周围网的改变。

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2025-02-01 DOI: 10.1016/j.nbd.2024.106776

Héctor Cañeque-Rufo , Teresa Fontán-Baselga , Milagros Galán-Llario , Agata Zuccaro , María Gracia Sánchez-Alonso , Esther Gramage , María del Pilar Ramos-Álvarez , Gonzalo Herradón

Obesity and metabolic disorders, such as metabolic syndrome (MetS) facilitate the development of neurodegenerative diseases and cognitive decline. Persistent neuroinflammation plays an important role in this process. Pleiotrophin (PTN) is a cytokine that regulates energy metabolism and high-fat diet (HFD)-induced neuroinflammation, suggesting that PTN could play an important role in the connection between obesity and brain alterations, including cognitive decline. To test this hypothesis, we used an HFD-induced obesity model in Ptn genetically deficient mice (Ptn^−/−). First, we confirmed that Ptn deletion prevents HFD-induced obesity. Our findings demonstrate that feeding wild-type (Ptn^+/+) mice with HFD for 6 months results in short- and long-term memory loss in the novel object recognition task. Surprisingly, we did not observe any sign of cognitive impairment in Ptn^−/− mice fed with HFD. In addition, we observed that HFD induced microglial responses, astrocyte depletion, and perineuronal nets (PNNs) alterations in Ptn^+/+ mice, while these effects of HFD were mostly prevented in Ptn^−/− mice. These results show a crucial role of PTN in metabolic responses and brain alterations induced by HFD and suggest the PTN signalling pathway as a promising therapeutic target for brain disorders associated with MetS.

肥胖和代谢紊乱，如代谢综合征（MetS）促进神经退行性疾病和认知能力下降的发展。持续的神经炎症在这一过程中起着重要作用。多营养蛋白（PTN）是一种调节能量代谢和高脂肪饮食（HFD）诱导的神经炎症的细胞因子，这表明PTN可能在肥胖和大脑改变（包括认知能力下降）之间的联系中发挥重要作用。为了验证这一假设，我们在Ptn基因缺陷小鼠（Ptn-/-）中使用了hfd诱导的肥胖模型。首先，我们证实Ptn缺失可以防止hfd诱导的肥胖。我们的研究结果表明，用HFD喂养野生型（Ptn+/+）小鼠6个月会导致新物体识别任务中的短期和长期记忆丧失。令人惊讶的是，在喂食HFD的Ptn-/-小鼠中，我们没有观察到任何认知障碍的迹象。此外，我们观察到HFD诱导Ptn+/+小鼠的小胶质细胞反应、星形胶质细胞消耗和神经周围网（PNNs）改变，而HFD在Ptn-/-小鼠中大多被阻止了这些影响。这些结果表明PTN在HFD诱导的代谢反应和脑改变中起着至关重要的作用，并表明PTN信号通路是与MetS相关的脑疾病的有希望的治疗靶点。

{"title":"Pleiotrophin deletion prevents high-fat diet-induced cognitive impairment, glial responses, and alterations of the perineuronal nets in the hippocampus","authors":"Héctor Cañeque-Rufo , Teresa Fontán-Baselga , Milagros Galán-Llario , Agata Zuccaro , María Gracia Sánchez-Alonso , Esther Gramage , María del Pilar Ramos-Álvarez , Gonzalo Herradón","doi":"10.1016/j.nbd.2024.106776","DOIUrl":"10.1016/j.nbd.2024.106776","url":null,"abstract":"<div><div>Obesity and metabolic disorders, such as metabolic syndrome (MetS) facilitate the development of neurodegenerative diseases and cognitive decline. Persistent neuroinflammation plays an important role in this process. Pleiotrophin (PTN) is a cytokine that regulates energy metabolism and high-fat diet (HFD)-induced neuroinflammation, suggesting that PTN could play an important role in the connection between obesity and brain alterations, including cognitive decline. To test this hypothesis, we used an HFD-induced obesity model in <em>Ptn</em> genetically deficient mice (<em>Ptn</em><sup>−/−</sup>). First, we confirmed that <em>Ptn</em> deletion prevents HFD-induced obesity. Our findings demonstrate that feeding wild-type (<em>Ptn</em><sup>+/+</sup>) mice with HFD for 6 months results in short- and long-term memory loss in the novel object recognition task. Surprisingly, we did not observe any sign of cognitive impairment in <em>Ptn</em><sup>−/−</sup> mice fed with HFD. In addition, we observed that HFD induced microglial responses, astrocyte depletion, and perineuronal nets (PNNs) alterations in <em>Ptn</em><sup>+/+</sup> mice, while these effects of HFD were mostly prevented in <em>Ptn</em><sup>−/−</sup> mice. These results show a crucial role of PTN in metabolic responses and brain alterations induced by HFD and suggest the PTN signalling pathway as a promising therapeutic target for brain disorders associated with MetS.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"205 ","pages":"Article 106776"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896241","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}

引用次数: 0

GluN2D-containing NMDA receptors in parvalbumin neurons in the nucleus accumbens regulate nocifensive responses in neuropathic pain 伏隔核小白蛋白神经元中含有glun2d的NMDA受体调节神经性疼痛的伤害反应。

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2025-02-01 DOI: 10.1016/j.nbd.2024.106784

Sukanya G. Gakare , Gajanan P. Shelkar , Dinesh Y. Gawande, Ratnamala Pavuluri, Pauravi J. Gandhi, Shashank M. Dravid

Neuropathic pain presents a significant challenge, with its underlying mechanisms still not fully understood. Here, we investigated the role of GluN2C- and GluN2D-containing NMDA receptors in the development of neuropathic pain induced by cisplatin, a widely used chemotherapeutic agent. Through genetic and pharmacological strategies, we found that GluN2D-containing NMDA receptors play a targeted role in regulating cisplatin-induced neuropathic pain (CINP), while sparing inflammatory or acute pain responses. Specifically, both GluN2D knockout (KO) mice and pharmacological blockade of GluN2D-containing receptors produced robust reduction in mechanical nocifensive response in CINP. In contrast, GluN2C KO mice behaved similar to wildtype mice in CINP but showed reduced mechanical hypersensitivity in inflammatory pain. Using conditional KO strategy, we addressed the region- and cell-type involved in GluN2D-mediated changes in CINP. Animals with conditional deletion of GluN2D receptors from parvalbumin interneurons (PVIs) or local ablation of GluN2D from nucleus accumbens (NAc) displayed reduced mechanical hypersensitivity in CINP, underscoring the pivotal role of accumbal GluN2D in PVIs in neuropathic pain. Furthermore, CINP increased excitatory neurotransmission in the NAc in wildtype mice and this effect is dampened in PV-GluN2D KO mice. Other changes in CINP in NAc included an increase in vGluT1 and c-fos labeled neurons in wildtype which were absent in PV-GluN2D KO mice. G_iDREADD-induced inhibition of PVIs in the NAc produced reduction in mechanical hypersensitivity in CINP. These findings unveil a novel cell-type and region-specific role of GluN2D-containing NMDA receptors in neuropathic pain and identify PVIs in NAc as a novel mediator of pain behaviors.

神经性疼痛提出了重大的挑战，其潜在的机制仍未完全了解。在这里，我们研究了GluN2C-和glun2d -含NMDA受体在顺铂（一种广泛使用的化疗药物）诱导的神经性疼痛发展中的作用。通过遗传和药理学策略，我们发现含有glun2d的NMDA受体在调节顺铂诱导的神经性疼痛（CINP）中发挥靶向作用，同时避免炎症或急性疼痛反应。具体来说，GluN2D敲除（KO）小鼠和含GluN2D受体的药物阻断均可显著降低CINP的机械伤害反应。相比之下，GluN2C KO小鼠在CINP中的表现与野生型小鼠相似，但在炎症性疼痛中表现出较低的机械超敏反应。使用条件KO策略，我们研究了glun2d介导的CINP变化所涉及的区域和细胞类型。小白蛋白中间神经元（PVIs） GluN2D受体条件缺失或伏隔核（NAc） GluN2D局部消融的动物在CINP中表现出机械超敏性降低，强调了PVIs中伏隔GluN2D在神经性疼痛中的关键作用。此外，CINP增加了野生型小鼠NAc的兴奋性神经传递，而这种作用在PV-GluN2D KO小鼠中被抑制。NAc中CINP的其他变化包括野生型中vGluT1和c-fos标记神经元的增加，这些神经元在PV-GluN2D KO小鼠中不存在。gidreadd诱导的NAc中PVIs的抑制降低了CINP的机械超敏反应。这些发现揭示了含有glun2d的NMDA受体在神经性疼痛中的新细胞类型和区域特异性作用，并确定了NAc中的PVIs是疼痛行为的新介质。

{"title":"GluN2D-containing NMDA receptors in parvalbumin neurons in the nucleus accumbens regulate nocifensive responses in neuropathic pain","authors":"Sukanya G. Gakare , Gajanan P. Shelkar , Dinesh Y. Gawande, Ratnamala Pavuluri, Pauravi J. Gandhi, Shashank M. Dravid","doi":"10.1016/j.nbd.2024.106784","DOIUrl":"10.1016/j.nbd.2024.106784","url":null,"abstract":"<div><div>Neuropathic pain presents a significant challenge, with its underlying mechanisms still not fully understood. Here, we investigated the role of GluN2C- and GluN2D-containing NMDA receptors in the development of neuropathic pain induced by cisplatin, a widely used chemotherapeutic agent. Through genetic and pharmacological strategies, we found that GluN2D-containing NMDA receptors play a targeted role in regulating cisplatin-induced neuropathic pain (CINP), while sparing inflammatory or acute pain responses. Specifically, both GluN2D knockout (KO) mice and pharmacological blockade of GluN2D-containing receptors produced robust reduction in mechanical nocifensive response in CINP. In contrast, GluN2C KO mice behaved similar to wildtype mice in CINP but showed reduced mechanical hypersensitivity in inflammatory pain. Using conditional KO strategy, we addressed the region- and cell-type involved in GluN2D-mediated changes in CINP. Animals with conditional deletion of GluN2D receptors from parvalbumin interneurons (PVIs) or local ablation of GluN2D from nucleus accumbens (NAc) displayed reduced mechanical hypersensitivity in CINP, underscoring the pivotal role of accumbal GluN2D in PVIs in neuropathic pain. Furthermore, CINP increased excitatory neurotransmission in the NAc in wildtype mice and this effect is dampened in PV-GluN2D KO mice. Other changes in CINP in NAc included an increase in vGluT1 and c-fos labeled neurons in wildtype which were absent in PV-GluN2D KO mice. G<sub>i</sub>DREADD-induced inhibition of PVIs in the NAc produced reduction in mechanical hypersensitivity in CINP. These findings unveil a novel cell-type and region-specific role of GluN2D-containing NMDA receptors in neuropathic pain and identify PVIs in NAc as a novel mediator of pain behaviors.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"205 ","pages":"Article 106784"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142903498","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}

引用次数: 0

Haploinsufficiency of PDE2A causes in mice increased exploratory behavior associated with upregulation of neural nitric oxide synthase in the striatum PDE2A单倍体不足导致小鼠探索行为增加，这与纹状体中神经一氧化氮合酶的上调有关。

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2025-02-01 DOI: 10.1016/j.nbd.2024.106781

Ana Gabriela de Oliveira do Rêgo , Francesca D'Amico , Vincenza D’Angelo , Silvia Cardarelli , Debora Cutuli , Davide Decandia , Eugenia Landolfo , Laura Petrosini , Manuela Pellegrini , Marcello D’Amelio , Nicola Biagio Mercuri , Mauro Giorgi , Giuseppe Sancesario

Phosphodiesterase 2 A (PDE2A) function is stimulated by cGMP to catabolize cAMP. However, neurological and neurochemical effects of PDE2A deficiency are poorly understood. To address this gap, we studied behavioral characteristics and cerebral morpho-chemical changes of adult male heterozygous C57BL/6-PDE2A+/− (HET), and wild type C57BL/6-PDE2A+/+ (WT) mice.

Behavioral functions of mice were evaluated by a wide test battery. HET mice exhibited greater tendency to explore novel environments in comparison to WT mice, but spatial working memory, anxiety, and sociability were similar in adult HET and WT mice.

In HET mice, PDE2A mRNA, PDE2A protein expression, and cGMP hydrolyzing enzymatic activity were consistently reduced by about 50 %. Consequently, the cyclic nucleotide levels were significantly increased in HET mice, but unexpectedly the mean percentage variation was higher for cGMP equal to 153.23 %, and lower for cAMP equal to 16.41 %. Therefore, to try to explain the preponderant increase of cGMP to cAMP we evaluated other PDE enzymes functionally related to PDE2A. Surprisingly, results were quite contradictory: in HET mice protein levels of the other dual-specificity enzyme PDE3A and PDE10A were reduced, whereas the expressions of PDE5A and PDE9A that selectively hydrolyze cGMP were increased.

Therefore, we investigated the involvement of neuronal nitric oxide synthase (nNOS) expression, as determinant of a possible increased synthesis of NO/cGMP signaling. Interestingly, in HET mice the expression level of brain nNOS, measured by western blot and immune-histochemistry was significantly increased, particularly in interneurons from the striatum.

In conclusion, the deficiency of PDE2A could be compensated in the striatum by upregulating nNOS/NO/cGMP pathway, which in turn likely upregulates PDE2A-dependent cAMP hydrolysis. The neuroanatomical correlation between striatal nNOS upregulation and the behavioral phenotype of increased exploratory behavior in HET mice is advanced.

磷酸二酯酶2 A （PDE2A）功能在cGMP的刺激下分解cAMP。然而，PDE2A缺乏对神经和神经化学的影响尚不清楚。为了弥补这一空白，我们研究了成年雄性杂合C57BL/6-PDE2A+/- (HET)和野生型C57BL/6-PDE2A+/+ (WT)小鼠的行为特征和大脑形态化学变化。采用大范围试验电池评价小鼠的行为功能。与WT小鼠相比，HET小鼠表现出更大的探索新环境的倾向，但空间工作记忆、焦虑和社交能力在成年HET小鼠和WT小鼠中相似。在HET小鼠中，PDE2A mRNA、PDE2A蛋白表达和cGMP水解酶活性持续降低约50% %。因此，HET小鼠的环核苷酸水平显著升高，但出乎意料的是，cGMP的平均百分比变化较高，为153.23 %，cAMP的平均百分比变化较低，为16.41 %。因此，为了试图解释cGMP对cAMP的显著增加，我们评估了与PDE2A功能相关的其他PDE酶。令人惊讶的是，结果非常矛盾：在HET小鼠中，其他双特异性酶PDE3和PDE10A的蛋白水平降低，而选择性水解cGMP的PDE5和PDE9的表达增加。因此，我们研究了神经元一氧化氮合酶（nNOS）表达的参与，作为NO/cGMP信号合成可能增加的决定因素。有趣的是，通过western blot和免疫组织化学检测，HET小鼠脑nNOS的表达水平显著增加，尤其是纹状体的中间神经元。综上所述，纹状体中PDE2A的缺失可以通过上调nNOS/NO/cGMP通路来补偿，而nNOS/NO/cGMP通路又可能上调PDE2A依赖性cAMP水解。提出了HET小鼠纹状体nNOS上调与探索性行为增加的行为表型之间的神经解剖学相关性。

{"title":"Haploinsufficiency of PDE2A causes in mice increased exploratory behavior associated with upregulation of neural nitric oxide synthase in the striatum","authors":"Ana Gabriela de Oliveira do Rêgo , Francesca D'Amico , Vincenza D’Angelo , Silvia Cardarelli , Debora Cutuli , Davide Decandia , Eugenia Landolfo , Laura Petrosini , Manuela Pellegrini , Marcello D’Amelio , Nicola Biagio Mercuri , Mauro Giorgi , Giuseppe Sancesario","doi":"10.1016/j.nbd.2024.106781","DOIUrl":"10.1016/j.nbd.2024.106781","url":null,"abstract":"<div><div>Phosphodiesterase 2 A (PDE2A) function is stimulated by cGMP to catabolize cAMP. However, neurological and neurochemical effects of PDE2A deficiency are poorly understood. To address this gap, we studied behavioral characteristics and cerebral morpho-chemical changes of adult male heterozygous C57BL/6-PDE2A+/− (HET), and wild type C57BL/6-PDE2A+/+ (WT) mice.</div><div>Behavioral functions of mice were evaluated by a wide test battery. HET mice exhibited greater tendency to explore novel environments in comparison to WT mice, but spatial working memory, anxiety, and sociability were similar in adult HET and WT mice.</div><div>In HET mice, PDE2A mRNA, PDE2A protein expression, and cGMP hydrolyzing enzymatic activity were consistently reduced by about 50 %. Consequently, the cyclic nucleotide levels were significantly increased in HET mice, but unexpectedly the mean percentage variation was higher for cGMP equal to 153.23 %, and lower for cAMP equal to 16.41 %. Therefore, to try to explain the preponderant increase of cGMP to cAMP we evaluated other PDE enzymes functionally related to PDE2A. Surprisingly, results were quite contradictory: in HET mice protein levels of the other dual-specificity enzyme PDE3A and PDE10A were reduced, whereas the expressions of PDE5A and PDE9A that selectively hydrolyze cGMP were increased.</div><div>Therefore, we investigated the involvement of neuronal nitric oxide synthase (nNOS) expression, as determinant of a possible increased synthesis of NO/cGMP signaling. Interestingly, in HET mice the expression level of brain nNOS, measured by western blot and immune-histochemistry was significantly increased, particularly in interneurons from the striatum.</div><div>In conclusion, the deficiency of PDE2A could be compensated in the striatum by upregulating nNOS/NO/cGMP pathway, which in turn likely upregulates PDE2A-dependent cAMP hydrolysis. The neuroanatomical correlation between striatal nNOS upregulation and the behavioral phenotype of increased exploratory behavior in HET mice is advanced.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"205 ","pages":"Article 106781"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142903502","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}

引用次数: 0

Cerebellar lipid dysregulation in SCA3: A comparative study in patients and mice

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2025-02-01 DOI: 10.1016/j.nbd.2025.106827

Alexandra F. Putka , Varshasnata Mohanty , Stephanie M. Cologna , Hayley S. McLoughlin

Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia and belongs to the family of nine diseases caused by a polyglutamine expansion in the disease-causing protein. In SCA3, a polyglutamine expansion in ATXN3 causes neuron loss in disease-vulnerable brain regions, resulting in progressive loss of coordination and ultimately death. There are no disease-modifying or preventative treatments for this uniformly fatal disorder. Recent studies demonstrate prominent white matter atrophy and microstructural alterations in disease-vulnerable brain regions of SCA3 patients and mouse models. However, the major constituent of white matter – lipids – remains understudied in SCA3.

In this study, we conducted the first unbiased investigation of brain lipids in SCA3, focusing on the disease-vulnerable cerebellum of SCA3 postmortem patients and mouse models. Liquid chromatography-mass spectrometry uncovered widespread lipid reductions in patients with SCA3. Lipid downregulation was recapitulated in early- to mid-stage mouse models of SCA3, including transgenic YACQ84 and Knock-in Q300 mice. End-stage Knock-in Q300 mice displayed a progressive reduction in lipid content, highlighting targets that could benefit from early therapeutic intervention. In contrast, Atxn3-Knock-out mice showed mild lipid upregulation, emphasizing a toxic gain-of-function mechanism underlying lipid downregulation in SCA3.

We conclude that lipids are significantly altered in SCA3 and establish a platform for continued exploration of lipids in disease through interactive data visualization websites. Pronounced reductions in myelin-enriched lipids suggest that lipid dysregulation could underlie white matter atrophy in SCA3. This study establishes the basis for future work elucidating the mechanistic, biomarker, and therapeutic potential of lipids in SCA3.

{"title":"Cerebellar lipid dysregulation in SCA3: A comparative study in patients and mice","authors":"Alexandra F. Putka , Varshasnata Mohanty , Stephanie M. Cologna , Hayley S. McLoughlin","doi":"10.1016/j.nbd.2025.106827","DOIUrl":"10.1016/j.nbd.2025.106827","url":null,"abstract":"<div><div>Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia and belongs to the family of nine diseases caused by a polyglutamine expansion in the disease-causing protein. In SCA3, a polyglutamine expansion in ATXN3 causes neuron loss in disease-vulnerable brain regions, resulting in progressive loss of coordination and ultimately death. There are no disease-modifying or preventative treatments for this uniformly fatal disorder. Recent studies demonstrate prominent white matter atrophy and microstructural alterations in disease-vulnerable brain regions of SCA3 patients and mouse models. However, the major constituent of white matter – lipids – remains understudied in SCA3.</div><div>In this study, we conducted the first unbiased investigation of brain lipids in SCA3, focusing on the disease-vulnerable cerebellum of SCA3 postmortem patients and mouse models. Liquid chromatography-mass spectrometry uncovered widespread lipid reductions in patients with SCA3. Lipid downregulation was recapitulated in early- to mid-stage mouse models of SCA3, including transgenic YACQ84 and Knock-in Q300 mice. End-stage Knock-in Q300 mice displayed a progressive reduction in lipid content, highlighting targets that could benefit from early therapeutic intervention. In contrast, <em>Atxn3</em>-Knock-out mice showed mild lipid upregulation, emphasizing a toxic gain-of-function mechanism underlying lipid downregulation in SCA3.</div><div>We conclude that lipids are significantly altered in SCA3 and establish a platform for continued exploration of lipids in disease through interactive data visualization websites. Pronounced reductions in myelin-enriched lipids suggest that lipid dysregulation could underlie white matter atrophy in SCA3. This study establishes the basis for future work elucidating the mechanistic, biomarker, and therapeutic potential of lipids in SCA3.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"Article 106827"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123276","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}

引用次数: 0

Pleiotropic effects of mutant huntingtin on retinopathy in two mouse models of Huntington's disease 突变型亨廷顿蛋白对两种亨廷顿病小鼠视网膜病变的多效性影响。

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2025-02-01 DOI: 10.1016/j.nbd.2024.106780

Hui Xu, Anakha Ajayan, Ralf Langen, Jeannie Chen

Huntington's disease (HD) is caused by the expansion of a CAG repeat, encoding a string of glutamines (polyQ) in the first exon of the huntingtin gene (HTTex1). This mutant huntingtin protein (mHTT) with extended polyQ forms aggregates in cortical and striatal neurons, causing cell damage and death. The retina is part of the central nervous system (CNS), and visual deficits and structural abnormalities in the retina of HD patients have been observed. Defects in retinal structure and function are also present in the R6/2 and R6/1 HD transgenic mouse models that contain a gene fragment to express mHTTex1. We investigated whether these defects extend to the zQ175KI mouse model which is thought to be more representative of the human condition because it was engineered to contain the extended CAG repeat within the endogenous HTT locus. We found qualitatively similar phenotypes between R6/1 and zQ175KI retinae that include the presence of mHTT aggregates in retinal neurons, cone loss, downregulation of rod signaling proteins and abnormally elongated photoreceptor connecting cilia. In addition, we present novel findings that mHTT disrupts cell polarity in the photoreceptor cell layer and the retinal pigment epithelium (RPE). Furthermore, we show that the RPE cells from R6/1 mice contain mHTT nuclear inclusions, adding to the list of non-neuronal cells with mHTT aggregates and pathology. Thus, the eye may serve as a useful system to track disease progression and to test therapeutic intervention strategies for HD.

亨廷顿氏病（HD）是由CAG重复序列扩增引起的，该重复序列编码亨廷顿基因（HTTex1）的第一个外显子中的谷氨酰胺（polyQ）串。这种突变的亨廷顿蛋白（mHTT）具有扩展的多q，在皮层和纹状体神经元中形成聚集体，导致细胞损伤和死亡。视网膜是中枢神经系统（CNS）的一部分，已经观察到HD患者视网膜的视觉缺陷和结构异常。在含有表达mHTTex1基因片段的R6/2和R6/1 HD转基因小鼠模型中也存在视网膜结构和功能缺陷。我们研究了这些缺陷是否延伸到zQ175KI小鼠模型，该模型被认为更能代表人类的情况，因为它被设计成在内源性HTT位点内包含扩展的CAG重复序列。我们在R6/1和zQ175KI视网膜之间发现了质量上相似的表型，包括视网膜神经元中mHTT聚集体的存在，锥体丢失，杆状信号蛋白下调以及连接纤毛的光感受器异常延长。此外，我们提出了新的发现，mHTT破坏了感光细胞层和视网膜色素上皮（RPE）的细胞极性。此外，我们发现来自R6/1小鼠的RPE细胞含有mHTT核包裹体，增加了具有mHTT聚集和病理的非神经元细胞列表。因此，眼睛可以作为追踪疾病进展和测试HD治疗干预策略的有用系统。

{"title":"Pleiotropic effects of mutant huntingtin on retinopathy in two mouse models of Huntington's disease","authors":"Hui Xu, Anakha Ajayan, Ralf Langen, Jeannie Chen","doi":"10.1016/j.nbd.2024.106780","DOIUrl":"10.1016/j.nbd.2024.106780","url":null,"abstract":"<div><div>Huntington's disease (HD) is caused by the expansion of a CAG repeat, encoding a string of glutamines (polyQ) in the first exon of the huntingtin gene (HTTex1). This mutant huntingtin protein (mHTT) with extended polyQ forms aggregates in cortical and striatal neurons, causing cell damage and death. The retina is part of the central nervous system (CNS), and visual deficits and structural abnormalities in the retina of HD patients have been observed. Defects in retinal structure and function are also present in the R6/2 and R6/1 HD transgenic mouse models that contain a gene fragment to express mHTTex1. We investigated whether these defects extend to the zQ175KI mouse model which is thought to be more representative of the human condition because it was engineered to contain the extended CAG repeat within the endogenous HTT locus. We found qualitatively similar phenotypes between R6/1 and zQ175KI retinae that include the presence of mHTT aggregates in retinal neurons, cone loss, downregulation of rod signaling proteins and abnormally elongated photoreceptor connecting cilia. In addition, we present novel findings that mHTT disrupts cell polarity in the photoreceptor cell layer and the retinal pigment epithelium (RPE). Furthermore, we show that the RPE cells from R6/1 mice contain mHTT nuclear inclusions, adding to the list of non-neuronal cells with mHTT aggregates and pathology. Thus, the eye may serve as a useful system to track disease progression and to test therapeutic intervention strategies for HD.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"205 ","pages":"Article 106780"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907436","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}

引用次数: 0

Astrocytic NLRP3 cKO mitigates depression-like behaviors induced by mild TBI in mice. 星形细胞NLRP3 cKO减轻小鼠轻度TBI诱导的抑郁样行为。

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2025-02-01 DOI: 10.1016/j.nbd.2024.106785

Hui-Tao Miao , Jun Wang , Jing-Jing Shao , Rong-Xin Song , Wen-Guang Li , Jian-Kai Sun , Shi-Yan Jia , Dong-Xue Zhang , Xiao-Ming Li , Jian-Yong Zhao , Li-Min Zhang

Background

Reports indicate that depression is a common mental health issue following traumatic brain injury (TBI). Our prior research suggests that Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-related neuroinflammation, modulated by glial cells such as astrocytes, is likely to play a crucial role in the progression of anxiety and cognitive dysfunction. However, there is limited understanding of the potential of astrocytic NLRP3 in treating depression under mild TBI condition. This study aimed to determine whether astrocytic NLRP3 knockout (KO) could mitigate depressive-like behaviors following mild TBI and explore potential variations in such behaviors between genders post-mild TBI.

Methods

Mild TBI was induced in mice using Feeney's weight-drop method. Behavioral assessments included neurological severity scores (NSS), social interaction test (SI), tail suspension test (TST), and forced swimming test (FST). Pathological changes were evaluated through immunofluorescence and local field potential (LFP) recordings at various time points post-injury.

Results

Our findings indicated that astrocyte-specific NLRP3 KO decreased cleaved caspase-1 colocalized with astrocytes, decreased pathogenic astrocytes and increased Postsynaptic density protein 95 (PSD95) intensity, and significantly alleviated mild TBI-induced depression-like behaviors. It also led to the upregulation of protective astrocytes and apoptosis-associated factors, including cleaved caspase-3 post-mild TBI. Additionally, astrocyte-specific NLRP3 deletion resulting in improved θ and γ power and θ-γ phase coupling in the social interaction test (SI). Notably, under mild TBI conditions, astrocyte-specific NLRP3 exhibited greater neuroprotective effects in female knockout mice compared to males.

Conclusion

Astrocyte NLRP3 knockout demonstrated a protective mechanism in mice subjected to mild TBI, possibly attributed to the inhibition of pyroptosis through the NLRP3 signaling pathway in astrocytes.

背景：报告表明抑郁症是创伤性脑损伤（TBI）后常见的心理健康问题。我们之前的研究表明，由星形胶质细胞等神经胶质细胞调节的核苷酸结合寡聚化结构域样受体蛋白3 （NLRP3）相关的神经炎症可能在焦虑和认知功能障碍的进展中发挥关键作用。然而，对于星形细胞NLRP3治疗轻度创伤性脑损伤抑郁症的潜力了解有限。本研究旨在确定星形细胞NLRP3基因敲除（KO）是否可以减轻轻度脑外伤后的抑郁样行为，并探讨轻度脑外伤后这种行为在性别之间的潜在差异。方法：采用Feeney减重法诱导小鼠轻度TBI。行为评估包括神经系统严重程度评分（NSS）、社会互动测试（SI）、悬尾测试（TST）和强迫游泳测试（FST）。通过免疫荧光和局部场电位（LFP）记录损伤后各时间点的病理变化。结果：我们的研究结果表明，星形胶质细胞特异性NLRP3 KO降低了与星形胶质细胞共定位的cleaved caspase-1，减少了致病性星形胶质细胞，增加了突触后密度蛋白95 （PSD95）的强度，显著减轻了轻度脑损伤诱导的抑郁样行为。它还导致轻度TBI后保护性星形胶质细胞和凋亡相关因子上调，包括cleaved caspase-3。此外，星形胶质细胞特异性NLRP3缺失导致社会互动测试（SI）中θ和γ功率和θ-γ相耦合改善。值得注意的是，在轻度TBI条件下，与雄性相比，雌性敲除小鼠中星形胶质细胞特异性NLRP3表现出更大的神经保护作用。结论：敲除星形胶质细胞NLRP3对轻度脑外伤小鼠具有保护作用，可能与星形胶质细胞NLRP3信号通路抑制焦亡有关。

{"title":"Astrocytic NLRP3 cKO mitigates depression-like behaviors induced by mild TBI in mice.","authors":"Hui-Tao Miao , Jun Wang , Jing-Jing Shao , Rong-Xin Song , Wen-Guang Li , Jian-Kai Sun , Shi-Yan Jia , Dong-Xue Zhang , Xiao-Ming Li , Jian-Yong Zhao , Li-Min Zhang","doi":"10.1016/j.nbd.2024.106785","DOIUrl":"10.1016/j.nbd.2024.106785","url":null,"abstract":"<div><h3>Background</h3><div>Reports indicate that depression is a common mental health issue following traumatic brain injury (TBI). Our prior research suggests that Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-related neuroinflammation, modulated by glial cells such as astrocytes, is likely to play a crucial role in the progression of anxiety and cognitive dysfunction. However, there is limited understanding of the potential of astrocytic NLRP3 in treating depression under mild TBI condition. This study aimed to determine whether astrocytic NLRP3 knockout (KO) could mitigate depressive-like behaviors following mild TBI and explore potential variations in such behaviors between genders post-mild TBI.</div></div><div><h3>Methods</h3><div>Mild TBI was induced in mice using Feeney's weight-drop method. Behavioral assessments included neurological severity scores (NSS), social interaction test (SI), tail suspension test (TST), and forced swimming test (FST). Pathological changes were evaluated through immunofluorescence and local field potential (LFP) recordings at various time points post-injury.</div></div><div><h3>Results</h3><div>Our findings indicated that astrocyte-specific NLRP3 KO decreased cleaved caspase-1 colocalized with astrocytes, decreased pathogenic astrocytes and increased Postsynaptic density protein 95 (PSD95) intensity, and significantly alleviated mild TBI-induced depression-like behaviors. It also led to the upregulation of protective astrocytes and apoptosis-associated factors, including cleaved caspase-3 post-mild TBI. Additionally, astrocyte-specific NLRP3 deletion resulting in improved θ and γ power and θ-γ phase coupling in the social interaction test (SI). Notably, under mild TBI conditions, astrocyte-specific NLRP3 exhibited greater neuroprotective effects in female knockout mice compared to males.</div></div><div><h3>Conclusion</h3><div>Astrocyte NLRP3 knockout demonstrated a protective mechanism in mice subjected to mild TBI, possibly attributed to the inhibition of pyroptosis through the NLRP3 signaling pathway in astrocytes.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"205 ","pages":"Article 106785"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142966101","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}

引用次数: 0

Synaptic modulation of glutamate in striatum of the YAC128 mouse model of Huntington disease YAC128亨廷顿病小鼠纹状体中谷氨酸的突触调节。

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2025-02-01 DOI: 10.1016/j.nbd.2024.106774

Judy Cheng , Ellen T. Koch , Daniel Ramandi , James P. Mackay , Timothy P. O’Leary , William Rees-Jones , Lynn A. Raymond

Background

Altered balance between striatal direct and indirect pathways contributes to early motor, cognitive and psychiatric symptoms in Huntington disease (HD). While degeneration of striatal D2-type dopamine receptor (D2)-expressing indirect pathway medium spiny neurons (iMSNs) occurs prior to that of D1-type dopamine receptor (D1)-expressing direct pathway neurons, altered corticostriatal synaptic function precedes degeneration. D2-mediated signaling on iMSNs reduces their excitability and promotes endocannabinoid (eCB) synthesis, suppressing glutamate release from cortical afferents. D2 receptors are also expressed on glutamatergic cortical terminals, cholinergic interneurons, and dopaminergic terminals from substantia nigra where they suppress release of glutamate, acetylcholine and dopamine, respectively, and these cell types may contribute to early striatal dysfunction in HD. Thus, we used corticostriatal brain slices and optogenetic probes to directly investigate neuromodulatory signaling in the transgenic YAC128 HD mouse model.

Results

Low-dose D2 agonist quinpirole reduced cortically-evoked glutamate release in dorsal striatum of premanifest YAC128 slices but not WT, and blocking type 1 cannabinoid receptors mitigated this effect. YAC128 corticostriatal brain slices also showed increased evoked dopamine and reduced evoked eCB release compared to WT, while acetylcholine signaling patterns remained relatively intact.

Conclusions

These findings suggest that YAC128 corticostriatal slices show increased D2 sensitivity that is eCB-dependent, and that dopamine and eCB release are altered at an early disease stage. We provide evidence for impaired neuromodulatory signaling in early HD, guiding therapeutic efforts prior to the onset of overt motor symptoms later on.

背景：纹状体直接和间接通路之间平衡的改变有助于亨廷顿病（HD）的早期运动、认知和精神症状。虽然纹状体D2型表达多巴胺受体（D2）的间接通路中棘神经元（iMSNs）的变性发生在D1型表达多巴胺受体（D1）的直接通路神经元之前，但皮质纹状体突触功能的改变发生在变性之前。d2介导的iMSNs信号传导降低其兴奋性，促进内源性大麻素（eCB）合成，抑制皮层传入神经中谷氨酸的释放。D2受体也表达于谷氨酸能皮质末梢、胆碱能中间神经元和多巴胺能末梢，分别抑制谷氨酸、乙酰胆碱和多巴胺的释放，这些细胞类型可能与HD早期纹状体功能障碍有关。因此，我们使用皮质纹状体脑切片和光遗传学探针直接研究转基因YAC128 HD小鼠模型中的神经调节信号。结果：低剂量D2激动剂喹匹罗减少了YAC128预显片背纹状体皮质诱发的谷氨酸释放，但对WT没有作用，阻断1型大麻素受体减轻了这一作用。与WT相比，YAC128皮质纹状体脑切片也显示诱发多巴胺增加，诱发eCB释放减少，而乙酰胆碱信号模式保持相对完整。结论：这些发现表明，YAC128皮质纹状体切片显示D2敏感性增加，这是eCB依赖性的，多巴胺和eCB释放在疾病早期发生改变。我们提供了早期HD神经调节信号受损的证据，指导了后来出现明显运动症状之前的治疗努力。

{"title":"Synaptic modulation of glutamate in striatum of the YAC128 mouse model of Huntington disease","authors":"Judy Cheng , Ellen T. Koch , Daniel Ramandi , James P. Mackay , Timothy P. O’Leary , William Rees-Jones , Lynn A. Raymond","doi":"10.1016/j.nbd.2024.106774","DOIUrl":"10.1016/j.nbd.2024.106774","url":null,"abstract":"<div><h3>Background</h3><div>Altered balance between striatal direct and indirect pathways contributes to early motor, cognitive and psychiatric symptoms in Huntington disease (HD). While degeneration of striatal D2-type dopamine receptor (D2)-expressing indirect pathway medium spiny neurons (iMSNs) occurs prior to that of D1-type dopamine receptor (D1)-expressing direct pathway neurons, altered corticostriatal synaptic function precedes degeneration. D2-mediated signaling on iMSNs reduces their excitability and promotes endocannabinoid (eCB) synthesis, suppressing glutamate release from cortical afferents. D2 receptors are also expressed on glutamatergic cortical terminals, cholinergic interneurons, and dopaminergic terminals from substantia nigra where they suppress release of glutamate, acetylcholine and dopamine, respectively, and these cell types may contribute to early striatal dysfunction in HD. Thus, we used corticostriatal brain slices and optogenetic probes to directly investigate neuromodulatory signaling in the transgenic YAC128 HD mouse model.</div></div><div><h3>Results</h3><div>Low-dose D2 agonist quinpirole reduced cortically-evoked glutamate release in dorsal striatum of premanifest YAC128 slices but not WT, and blocking type 1 cannabinoid receptors mitigated this effect. YAC128 corticostriatal brain slices also showed increased evoked dopamine and reduced evoked eCB release compared to WT, while acetylcholine signaling patterns remained relatively intact.</div></div><div><h3>Conclusions</h3><div>These findings suggest that YAC128 corticostriatal slices show increased D2 sensitivity that is eCB-dependent, and that dopamine and eCB release are altered at an early disease stage. We provide evidence for impaired neuromodulatory signaling in early HD, guiding therapeutic efforts prior to the onset of overt motor symptoms later on.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"205 ","pages":"Article 106774"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882328","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}

引用次数: 0

Globular-shaped Aβ oligomers have diverse mechanisms for promoting Aβ aggregations with the facilitation of fibril elongation 球状Aβ低聚物具有促进Aβ聚集和促进纤维伸长的多种机制。

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2025-02-01 DOI: 10.1016/j.nbd.2024.106775

Hiroto Nakano , Sadao Hikishima , Makoto Mori , Jota Minamikawa , Daiki Muramatsu , Yasuhiro Sakashita , Tokuhei Ikeda , Moeko Noguchi-Shinohara , David B. Teplow , Kenjiro Ono

The accumulation of amyloid β-proteins (Aβ) in the extracellular space, forming insoluble plaques, is a primary pathological process underlying Alzheimer's disease (AD). Among the various Aβ species that appear during Aβ aggregation, Aβ oligomers are considered the most neurotoxic form. However, the precise mechanisms of their molecular functions within the Aβ aggregation cascade have not been clarified so far. This research aimed to uncover the structural and functional characteristics of globular-shaped Aβ oligomers (gAβO) under in vitro conditions. We performed thioflavin T (ThT) assays on low-molecular-weight (LMW) Aβ42, testing different concentrations of Aβ42 mature fibril (MF) seeds and gAβO. Fibril formation was continuously observed using high-speed atomic force microscopy (HS-AFM) in LMW Aβ42 with different sample conditions. Conformational changes of Aβ42 aggregates in the presence of gAβO was also evaluated using circular dichroism spectroscopy. The results of the ThT analysis and HS-AFM observation indicated that gAβO promoted fibril formation of LMW Aβ42 while gAβO itself did not form fibrous aggregates, indicating that gAβO would have a catalytic effects on LMW Aβ42 aggregation. We also showed that the molecular interaction of gAβO was altered by the presence and amount of MF seeds in the reaction buffers, indicating that complex interactions would exist among different Aβ species. The results of our present research demonstrated that gAβO would have significant roles to accelerate Aβ aggregation in AD pathogenesis.

225 < 250 words.

淀粉样β蛋白（a β）在细胞外空间积聚，形成不溶性斑块，是阿尔茨海默病（AD）的主要病理过程。在Aβ聚集过程中出现的各种Aβ物种中，Aβ低聚物被认为是最具神经毒性的形式。然而，它们在Aβ聚集级联中的分子功能的确切机制迄今尚未明确。本研究旨在揭示球形Aβ低聚物（gAβO）在体外条件下的结构和功能特征。我们对低分子量（LMW） Aβ42进行了硫黄素T （ThT）测定，检测了不同浓度的Aβ42成熟原纤维（MF）种子和a β o。利用高速原子力显微镜（HS-AFM）连续观察了不同样品条件下LMW a - β42的纤维形成情况。利用圆二色光谱分析了Aβ42聚集体在gAβO存在下的构象变化。ThT分析和HS-AFM观察结果表明，gAβO促进了LMW a - β42的纤维形成，而gAβO本身不形成纤维聚集体，说明gAβO对LMW a - β42的聚集具有催化作用。我们还发现，反应缓冲液中MF种子的存在和数量改变了Aβ o的分子相互作用，表明不同Aβ物种之间存在复杂的相互作用。我们目前的研究结果表明，gAβO可能在AD发病过程中具有显著的加速Aβ聚集的作用。225

{"title":"Globular-shaped Aβ oligomers have diverse mechanisms for promoting Aβ aggregations with the facilitation of fibril elongation","authors":"Hiroto Nakano , Sadao Hikishima , Makoto Mori , Jota Minamikawa , Daiki Muramatsu , Yasuhiro Sakashita , Tokuhei Ikeda , Moeko Noguchi-Shinohara , David B. Teplow , Kenjiro Ono","doi":"10.1016/j.nbd.2024.106775","DOIUrl":"10.1016/j.nbd.2024.106775","url":null,"abstract":"<div><div>The accumulation of amyloid β-proteins (Aβ) in the extracellular space, forming insoluble plaques, is a primary pathological process underlying Alzheimer's disease (AD). Among the various Aβ species that appear during Aβ aggregation, Aβ oligomers are considered the most neurotoxic form. However, the precise mechanisms of their molecular functions within the Aβ aggregation cascade have not been clarified so far. This research aimed to uncover the structural and functional characteristics of globular-shaped Aβ oligomers (gAβO) under in vitro conditions. We performed thioflavin T (ThT) assays on low-molecular-weight (LMW) Aβ42, testing different concentrations of Aβ42 mature fibril (MF) seeds and gAβO. Fibril formation was continuously observed using high-speed atomic force microscopy (HS-AFM) in LMW Aβ42 with different sample conditions. Conformational changes of Aβ42 aggregates in the presence of gAβO was also evaluated using circular dichroism spectroscopy. The results of the ThT analysis and HS-AFM observation indicated that gAβO promoted fibril formation of LMW Aβ42 while gAβO itself did not form fibrous aggregates, indicating that gAβO would have a catalytic effects on LMW Aβ42 aggregation. We also showed that the molecular interaction of gAβO was altered by the presence and amount of MF seeds in the reaction buffers, indicating that complex interactions would exist among different Aβ species. The results of our present research demonstrated that gAβO would have significant roles to accelerate Aβ aggregation in AD pathogenesis.</div><div>225 < 250 words.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"205 ","pages":"Article 106775"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886020","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}

引用次数: 0

Modeling sacsin depletion in Danio Rerio offers new insight on retinal defects in ARSACS 模拟Danio Rerio的囊蛋白损耗为ARSACS视网膜缺陷提供了新的见解。

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2025-02-01 DOI: 10.1016/j.nbd.2025.106793

Valentina Naef , Devid Damiani , Rosario Licitra , Maria Marchese , Stefania Della Vecchia , Matteo Baggiani , Letizia Brogi , Daniele Galatolo , Silvia Landi , Filippo Maria Santorelli

Biallelic mutations in the SACS gene, encoding sacsin, cause early-onset autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a neurodegenerative disease also characterized by unique and poorly understood retinal abnormalities. While two murine models replicate the phenotypic and neuronal features observed in patients, no retinal phenotype has been described so far. In a zebrafish knock-out strain that faithfully mirrors the main aspects of ARSACS, we observed impaired visual function due to photoreceptor degeneration, likely caused by cell cycle defects in progenitor cells. RNA-seq analysis in embryos revealed dysfunction in proteins related to fat-soluble vitamins (e.g., TTPA, RDH5, VKORC) and suggested a key role of neuroinflammation in driving the retinal defects. Our findings indicate that studying retinal pathology in ARSACS could be crucial for understanding the impact of sacsin depletion and may offer insights into halting disease progression.

编码sacins的SACS基因的双等位基因突变导致早发性常染色体隐性痉挛性共济失调（ARSACS），这是一种神经退行性疾病，也以独特且鲜为人知的视网膜异常为特征。虽然两种小鼠模型复制了在患者中观察到的表型和神经元特征，但迄今为止尚未描述视网膜表型。在一个真实反映ARSACS主要方面的斑马鱼敲除菌株中，我们观察到由于光感受器变性而导致的视觉功能受损，这可能是由祖细胞的细胞周期缺陷引起的。胚胎的RNA-seq分析显示，与脂溶性维生素相关的蛋白质（如TTPA、RDH5、VKORC）功能障碍，并提示神经炎症在驱动视网膜缺陷中的关键作用。我们的研究结果表明，研究ARSACS的视网膜病理对于理解sacin耗竭的影响至关重要，并可能为阻止疾病进展提供见解。

{"title":"Modeling sacsin depletion in Danio Rerio offers new insight on retinal defects in ARSACS","authors":"Valentina Naef , Devid Damiani , Rosario Licitra , Maria Marchese , Stefania Della Vecchia , Matteo Baggiani , Letizia Brogi , Daniele Galatolo , Silvia Landi , Filippo Maria Santorelli","doi":"10.1016/j.nbd.2025.106793","DOIUrl":"10.1016/j.nbd.2025.106793","url":null,"abstract":"<div><div>Biallelic mutations in the <em>SACS</em> gene, encoding sacsin, cause early-onset autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a neurodegenerative disease also characterized by unique and poorly understood retinal abnormalities. While two murine models replicate the phenotypic and neuronal features observed in patients, no retinal phenotype has been described so far. In a zebrafish <em>knock-out</em> strain that faithfully mirrors the main aspects of ARSACS, we observed impaired visual function due to photoreceptor degeneration, likely caused by cell cycle defects in progenitor cells. RNA-seq analysis in embryos revealed dysfunction in proteins related to fat-soluble vitamins (e.g., TTPA, RDH5, VKORC) and suggested a key role of neuroinflammation in driving the retinal defects. Our findings indicate that studying retinal pathology in ARSACS could be crucial for understanding the impact of sacsin depletion and may offer insights into halting disease progression.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"205 ","pages":"Article 106793"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11757156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952067","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}

引用次数: 0