Neurobiology of Disease最新文献_第9页

Huntingtin plays an essential role in the adult hippocampus

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2025-01-22 DOI: 10.1016/j.nbd.2025.106810

Jessica C. Barron , Laura J. Dawson , Samantha J. Carew , Mackenzie C. Grace , Kelsie A. Senior , Katelyn C. Ryan , Firoozeh Nafar , Craig S. Moore , Jacqueline Blundell , Matthew P. Parsons

The consequences of non-pathogenic huntingtin (HTT) reduction in the mature brain are of substantial importance as clinical trials for numerous HTT-lowering therapies are underway; many of which are non-selective in that they reduce both mutant and wild type protein variants. In this study, we injected CaMKII-promoted AAV-Cre directly into the hippocampus of adult HTT floxed mice to explore the role of wild-type huntingtin (wtHTT) in adult hippocampal pyramidal neurons and the broader implications of its loss. Our findings reveal that wtHTT depletion results in profound macroscopic morphological abnormalities in hippocampal structure, accompanied by significant reactive gliosis. At the synaptic level, we identified a marked reduction in presynaptic terminals 1–2 months following wtHTT loss; this was contrasted by an increased density of postsynaptic mushroom spines and larger amplitudes of spontaneous excitatory postsynaptic currents, indicative of disrupted synaptic homeostasis. Furthermore, intrinsic neuronal excitability was significantly diminished in CA1 pyramidal neurons lacking wtHTT, and we observed a complete loss of NMDA receptor-dependent long-term potentiation. Unexpectedly, synapse density returned to control levels 6–8 months following wtHTT loss, despite the ongoing presence of macroscopic morphological abnormalities, altered anxiety-related behaviors and clear impairments in spatial learning and memory. Overall, these findings uncover a previously unrecognized role of wtHTT as a critical regulator of hippocampal function in the mature brain, and highlight the hippocampus as a potentially vulnerable region to the adverse effects of non-selective HTT reduction.

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引用次数: 0

Resting-state electroencephalographic rhythms depend on sex in patients with dementia due to Parkinson's and Lewy Body diseases: An exploratory study

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2025-01-22 DOI: 10.1016/j.nbd.2025.106807

Claudio Del Percio , Roberta Lizio , Susanna Lopez , Giuseppe Noce , Dharmendra Jakhar , Matteo Carpi , Burcu Bölükbaş , Andrea Soricelli , Marco Salvatore , Bahar Güntekin , Görsev Yener , Federico Massa , Dario Arnaldi , Francesco Famà , Matteo Pardini , Raffaele Ferri , Michele Salerni , Bartolo Lanuzza , Fabrizio Stocchi , Laura Vacca , Claudio Babiloni

Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) are more prevalent in males than females. Furthermore, they typically showed abnormally high delta (< 4 Hz) and low alpha (8–10 Hz) rhythms from resting-state electroencephalographic (rsEEG) activity. Here, we hypothesized that those abnormalities may depend on the patient's sex.

An international database provided clinical-demographic-rsEEG datasets for cognitively unimpaired older (Healthy; N = 49; 24 females), PDD (N = 39; 13 females), and DLB (N = 38; 15 females) participants. Each group was stratified into matched female and male subgroups. The rsEEG rhythms were investigated across the individual rsEEG delta, theta, and alpha frequency bands based on the individual alpha frequency peak. The eLORETA freeware was used to estimate cortical rsEEG sources.

In the Healthy group, widespread rsEEG alpha source activities were greater in the females than in the males. In the PDD group, widespread rsEEG delta source activities were lower and widespread rsEEG alpha source activities were greater in the females than in the males. In the DLB group, central-parietal rsEEG delta source activities were lower, and posterior rsEEG alpha source activities were greater in the females than in the males.

These results suggest sex-dependent hormonal modulation of neuroprotective-compensatory neurophysiological mechanisms in PDD and DLB patients underlying the generation of rsEEG delta and alpha rhythms, which should be considered in the treatment of vigilance dysregulation in those patients.

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引用次数: 0

WTAP suppresses STAT3 via m6A methylation to regulate autophagy and inflammation in central nervous system injury

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2025-01-22 DOI: 10.1016/j.nbd.2025.106811

Xiaoyong Zhao , Xiaoli Zhang , Liangzhi Wu , Xiaohe Liu , Yongquan Pan , Taiquan Lv , Mingyang Xu , Kongbin Yang , Xiangyu Wang

Central nervous system (CNS) repair after injury is a challenging process limited by inflammation and neuronal apoptosis. This study identifies Wilms' tumor 1-associating protein (WTAP) as a pivotal regulator of neuronal protection and repair through m6A methylation of STAT3 mRNA. By employing spinal cord injury (SCI) as a representative model of CNS injury, transcriptomic analyses reveal WTAP as a key mediator of pathways related to neuronal autophagy and inflammation regulation. WTAP enhances neuronal autophagy by suppressing STAT3 expression and activity, which inhibits the NLRP3 inflammatory pathway. Functional studies demonstrate that WTAP knockdown exacerbates neuronal apoptosis, whereas overexpression improves cell viability, autophagy, and motor recovery. In vivo, WTAP promotes SCI repair via m6A-mediated suppression of STAT3 and regulation of the NLRP3 signaling pathway, highlighting its therapeutic potential for CNS injury repair.

引用次数: 0

Brain acid sphingomyelinase controls addiction-related behaviours in a sex-specific way 脑酸性鞘磷脂酶以一种性别特异性的方式控制成瘾相关行为。

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2025-01-17 DOI: 10.1016/j.nbd.2025.106800

Liubov S. Kalinichenko , Iulia Zoicas , Anne-Marie Bienia , Clara Bühner , Julia Robinson , Joshua Kütemeyer , Annika Labonte , Thadshajiny Raveendran , Lena Warth , Irena Smaga , Malgorzata Filip , Volker Eulenburg , Cosima Rhein , Anna Fejtova , Erich Gulbins , Johannes Kornhuber , Christian P. Müller

Addiction is a chronic and severe mental disorder with high gender- and sex-specificity. However, the pathogenesis of this disorder is not fully elucidated, and no targeted pharmacotherapy is available. A growing body of evidence points out the potential involvement of the ceramide system in the pathophysiology of addiction. A pathogenic pathway for several mental disorders based on the overexpression of an enzyme involved in ceramide formation, acid sphingomyelinase (ASM), was recently proposed. Here we show a crucial role of ASM specifically overexpressing in the forebrain for various types of addiction-related behaviours in a drug- and sex-specific way. In male mice, a forebrain ASM overexpression led to enhanced alcohol consumption in a free-choice paradigm. It also diminished the reinforcing properties of alcohol and cocaine, but not that of amphetamine, ketamine, or a natural reinforcer fat/carbohydrate-rich food in the conditioned place preference (CPP) test in males. In female mice, a forebrain ASM overexpression enhanced alcohol binge-like drinking, while moderate alcohol consumption was preserved. ASM overexpression in females contributed to CPP establishment for amphetamine, but not for other psychoactive substances. Altogether, this study shows a specific involvement of forebrain ASM in the development of conditioned reinforcing effects of different types of substances with addictive properties in a sex-specific way. Our data enlarge the current knowledge on the specific molecular mechanisms of dependence from various drugs of abuse and might serve as a basis for the development of drug- and sex-specific targeted therapy.

成瘾是一种慢性严重的精神障碍，具有高度的性别特异性和性别特异性。然而，这种疾病的发病机制尚未完全阐明，也没有靶向药物治疗。越来越多的证据表明神经酰胺系统可能参与成瘾的病理生理过程。最近提出了一种基于参与神经酰胺形成的酶——酸性鞘磷脂酶（ASM）的过度表达的几种精神障碍的致病途径。在这里，我们展示了ASM在前脑中以药物和性别特异性方式特异性过度表达的各种成瘾相关行为的关键作用。在雄性小鼠中，在自由选择模式下，前脑ASM过表达导致酒精消耗增加。在条件位置偏好（CPP）测试中，它也削弱了酒精和可卡因的强化特性，但没有削弱安非他明、氯胺酮或天然强化物脂肪/富含碳水化合物的食物。在雌性小鼠中，前脑ASM过表达增强了酒精狂饮样饮酒，而适度饮酒则保持不变。女性ASM过表达有助于安非他明的CPP建立，但对其他精神活性物质没有影响。总之，本研究表明，前脑ASM以性别特异性的方式参与了不同类型具有成瘾性质的物质的条件强化效应的发展。我们的数据扩大了目前对各种药物滥用依赖的特定分子机制的了解，并可能作为开发药物和性别特异性靶向治疗的基础。

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引用次数: 0

Downregulation of the NPY-Y1R system in Grpr neurons results in mechanical and chemical hyperknesis in chronic itch Grpr神经元中NPY-Y1R系统的下调导致慢性瘙痒的机械和化学亢进。

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2025-01-17 DOI: 10.1016/j.nbd.2025.106806

Danqing Dai , Zongxi Li , Tiantian Zhao, Zhen Li, Yali Tang, Xiujuan Li, Xiao-Fei Gao, Lize Xiong

Chronic itch remains a clinically challenging condition with limited therapeutic efficacy, posing a significant burden on patients' quality of life. Despite its prevalence, the underlying neural mechanisms remain poorly understood. In this study, we explored the synaptic relationships between neuropeptide Y (NPY) neurons and gastrin-releasing peptide receptor (GRPR) neurons in the spinal cord. Our findings reveal a direct synaptic connection whereby Npy neurons provide inhibitory modulation to Grpr neurons. Notably, during chronic itch, the activity of Grpr neurons was significantly elevated, coinciding with a decrease in Y1 receptor expression and a reduction in both the frequency and amplitude of inhibitory postsynaptic currents (IPSCs). These results suggest a decline in NPY/Y1R system function during chronic itch, leading to a decreased inhibitory influence of Npy neurons on Grpr neurons and subsequent disinhibition and excitation of the latter. This disinhibitory mechanism may underlie the enhanced responsiveness to mechanical and chemical itch stimuli in chronic itch patients.

慢性瘙痒仍然是一种具有临床挑战性的疾病，治疗效果有限，对患者的生活质量造成了重大负担。尽管它很普遍，但潜在的神经机制仍然知之甚少。在这项研究中，我们探讨了神经肽Y （NPY）神经元与脊髓胃泌素释放肽受体（GRPR）神经元之间的突触关系。我们的研究结果揭示了一种直接的突触连接，即Npy神经元对Grpr神经元提供抑制调节。值得注意的是，在慢性瘙痒期间，Grpr神经元的活性显著升高，与Y1受体表达减少以及抑制性突触后电流（IPSCs）的频率和幅度减少相一致。这些结果表明，在慢性瘙痒过程中，NPY/Y1R系统功能下降，导致NPY神经元对Grpr神经元的抑制作用下降，并导致后者的去抑制和兴奋。这种去抑制机制可能是慢性瘙痒患者对机械和化学瘙痒刺激反应增强的基础。

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引用次数: 0

Retraction Notice to “Differential effects of immunotherapy with antibodies targeting α-synuclein oligomers and fibrils in a transgenic model of synucleinopathy” [Neurobiology of Disease 104 (2017) 85–96] “针对α-突触核蛋白低聚物和原纤维的抗体免疫治疗在突触核蛋白病转基因模型中的差异效应”[j].神经生物学杂志，2017,85-96。

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2025-01-15 DOI: 10.1016/j.nbd.2025.106788

Omar El-Agnaf , Cassia Overk , Edward Rockenstein , Michael Mante , Jazmin Florio , Anthony Adame , Nishant Vaikath , Nour Majbour , Seung-Jae Lee , Changyoun Kim , Eliezer Masliah , Robert A. Rissman

引用次数: 0

Phosphorylated-tau associates with HSV-1 chromatin and correlates with nuclear speckles decondensation in low-density host chromatin regions 磷酸化的tau蛋白与HSV-1染色质相关，并与低密度宿主染色质区域的核斑点去浓缩相关。

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2025-01-14 DOI: 10.1016/j.nbd.2025.106804

Leonardo D'Aiuto , Jill K. Caldwell , Terri G. Edwards , Chaoming Zhou , Matthew L. McDonald , Roberto Di Maio , Wood A. Joel , Vanesa R. Hyde , Callen T. Wallace , Simon C. Watkins , Maribeth A. Wesesky , Or A. Shemesh , Vishwajit L. Nimgaonkar , David C. Bloom

Abnormal tau phosphorylation is a key mechanism in neurodegenerative diseases. Evidence implicates infectious agents, such as Herpes Simplex Virus 1 (HSV-1), as co-factors in the onset or the progression of neurodegenerative diseases, including Alzheimer's disease. This has led to divergence in the field regarding the contribution of viruses in the etiology of neurodegenerative diseases. Research indicates that viruses may function as risk factors driving neurodegenerative disease rather than playing a causative role. Investigating HSV-1 in abnormal tau phosphorylation is important for understanding the role of infectious agents in neurodegeneration.

We generated cellular models of HSV-1 acute, latent infection, and viral reactivation from latency in cortical brain organoids and investigated the interplay between tau phosphorylation and HSV-1 infection by employing human induced pluripotent stem cell (iPSC)-derived monolayer neuronal cultures and brain organoids. Acute infection with HSV-1 strains 17syn⁺ and KOS caused nuclear accumulation of phosphorylated tau (p-tau) in neurons and neural precursor cells. Antivirals prevented nuclear accumulation of p-tau. Viral reactivation was accompanied by the nuclear translocation of p-tau. Chromatin immunoprecipitation analysis indicated an interaction of p-tau with the viral chromatin. A reduction in abundance of component of nuclear speckles and their loss of organized morphology in low-denisty host chromatin regions was observed, with strain-specific differences. HSV-1 infection was followed by an increase in the abundance of BRSKs and TAOKs, kinases known to phosphorylate tau.

These findings show interaction between p-tau and HSV-1 chromatin and demonstrate the ability of HSV-1 to activate mechanisms that are observed in Alzheimer's disease.

异常的tau磷酸化是神经退行性疾病的关键机制。有证据表明，诸如单纯疱疹病毒1型（HSV-1）等传染因子是包括阿尔茨海默病在内的神经退行性疾病发病或进展的辅助因素。这导致了该领域关于病毒在神经退行性疾病病因学中的作用的分歧。研究表明，病毒可能是驱动神经退行性疾病的危险因素，而不是致病因素。研究HSV-1在异常tau磷酸化中的作用对于理解感染因子在神经变性中的作用是重要的。我们在脑皮质类器官中建立了HSV-1急性感染、潜伏感染和潜伏病毒再激活的细胞模型，并利用人诱导多能干细胞（iPSC）衍生的单层神经元培养物和脑类器官研究了tau磷酸化与HSV-1感染之间的相互作用。急性感染HSV-1毒株17syn+和KOS可引起神经元和神经前体细胞中磷酸化tau蛋白（p-tau）的核积累。抗病毒药物阻止了p-tau蛋白的核积累。病毒再激活伴随着p-tau的核易位。染色质免疫沉淀分析表明p-tau与病毒染色质相互作用。在低密度寄主染色质区域观察到核斑点成分丰度的减少及其有组织形态的丧失，具有菌株特异性差异。1型单纯疱疹病毒感染后，brsk和TAOKs的丰度增加，已知激酶磷酸化tau蛋白。这些发现显示了p-tau蛋白和单纯疱疹病毒-1染色质之间的相互作用，并证明了单纯疱疹病毒-1能够激活在阿尔茨海默病中观察到的机制。

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引用次数: 0

Fine social discrimination of siblings in mice: Implications for early detection of Alzheimer's disease 小鼠兄弟姐妹的良好社会歧视：对阿尔茨海默病早期检测的影响。

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2025-01-13 DOI: 10.1016/j.nbd.2025.106799

Lola M.P. Fauré, Sébastien Gauzin, Camille Lejards, Claire Rampon , Laure Verret

The ability to distinguish between individuals is crucial for social species and supports behaviors such as reproduction, hierarchy formation, and cooperation. In rodents, social discrimination relies on memory and the recognition of individual-specific cues, known as “individual signatures”. While olfactory signals are central, other sensory cues — such as auditory, visual, and tactile inputs — also play a role. However, little research has explored the fine discrimination of individuals with overlapping cues, such as siblings or cohabitating mice. This study investigates whether mice can discriminate between two closely related individuals: siblings from the same litter and cage. We tested the hypothesis that it would be more challenging for mice to distinguish between siblings than between unrelated mice due to shared cues. Moreover, social cognitive impairments are common in neurodegenerative diseases like Alzheimer's disease (AD), where difficulties in recognizing faces and voices progressively disrupt social interactions in patients. Using a mouse model of AD (Tg2576), known for the progressive onset of cognitive deficits, we assessed whether the ability to discriminate between siblings is preserved in “pre-symptomatic” animals. Thus, we first demonstrated that male and female C57BL6/J mice can discriminate siblings, regardless of sex. Next, we revealed that “pre-symptomatic” 3-month-old Tg2576 mice exhibit impairments in fine social memory, while their general social memory remains unaffected. Thus, we demonstrate that the inability to perform fine social discrimination is an early cognitive impairment that arises before other well-documented memory abnormalities in this AD mouse model.

区分个体的能力对群居物种来说至关重要，并支持着繁殖、等级形成和合作等行为。在啮齿类动物中，社会歧视依赖于记忆和对个体特定线索的识别，即“个体特征”。虽然嗅觉信号是核心，但其他感官信号——如听觉、视觉和触觉输入——也起着作用。然而，很少有研究探索具有重叠线索的个体的精细区分，例如兄弟姐妹或同居的老鼠。本研究调查了小鼠是否能够区分两个关系密切的个体：来自同一窝和同一笼的兄弟姐妹。我们测试了一个假设，即由于共享线索，老鼠区分兄弟姐妹比区分不相关的老鼠更具挑战性。此外，社会认知障碍在阿尔茨海默病（AD）等神经退行性疾病中很常见，在这种疾病中，识别面孔和声音的困难会逐渐破坏患者的社会互动。使用以认知缺陷进行性发作而闻名的AD小鼠模型（Tg2576），我们评估了在“症状前”动物中是否保留了区分兄弟姐妹的能力。因此，我们首次证明雄性和雌性C57BL6/J小鼠可以不分性别地区分兄弟姐妹。接下来，我们揭示了“症状前”3个月大的Tg2576小鼠在精细社会记忆方面表现出损伤，而它们的一般社会记忆没有受到影响。因此，我们证明，在AD小鼠模型中，无法进行良好的社会辨别是一种早期认知障碍，在其他有充分记录的记忆异常之前出现。

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引用次数: 0

Reconfigured metabolism brain network in asymptomatic Creutzfeldt-Jakob disease 无症状克雅氏病的脑代谢网络重构。

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2025-01-13 DOI: 10.1016/j.nbd.2025.106805

Yu Kong , Zhongyun Chen , Jing Zhang , Yihao Wang , Min Chu , Haitian Nan , Yue Cui , Deming Jiang , Liyong Wu

Background

Investigating brain metabolic networks is crucial for understanding the pathogenesis and functional alterations in Creutzfeldt-Jakob disease (CJD). However, studies on presymptomatic individuals remain limited. This study aimed to examine metabolic network topology reconfiguration in asymptomatic carriers of the PRNP G114V mutation.

Methods

Seven asymptomatic PRNP G114V mutation carriers from a familial genetic CJD (gCJD) cohort, 43 CJD patients, and 35 healthy controls were included. All participants underwent neuropsychological assessments, genetic testing, and ¹⁸F-fluorodeoxyglucose positron emission tomography (18F-FDG PET)/MRI scans. Voxel-based gray matter volume and FDG PET standardized uptake value ratios (SUVRs) were analyzed between asymptomatic PRNP G114V mutation carriers and healthy controls and between CJD patients and controls. Graph theory and sparse inverse covariance estimation (SICE) were used to assess the whole-brain metabolic connectomes and topological properties. Spatial independent component analysis (ICA) was used to evaluate subnetworks, including the default mode network (DMN), salience network (SN), and central executive network (CEN).

Results

With respect to global properties, assortativity was significantly increased in asymptomatic carriers, which was consistent with the findings in CJD patients. We revealed lost hubs in the right anterior cingulate, left ventral prefrontal lobe, left parahippocampal gyrus, and left lingual gyrus and reconfigured hubs in prefrontal lobes, including right ventromedial prefrontal cortex, right anterior prefrontal cortex, and right middle frontal gyrus of the orbit in asymptomatic carriers compared with healthy controls, which overlapped with the comparisons between CJD patients and controls. Alterations in the local parameters and metabolic connectivity in the left parahippocampal gyrus were most pronounced. Among the subnetworks, asymptomatic carriers presented higher assortativity and lower hierarchy in the SN, whereas the global parameters of the DMN and CEN were not significantly altered. The DMN and SN showed partial hypoconnectivity and hyperconnectivity, whereas the CEN mainly showed significantly enhanced connectivity in asymptomatic PRNP carriers.

Conclusions

This study revealed altered brain metabolic topology and connectomics in asymptomatic PRNP G114V mutation carriers, which could be detected before gray matter or regional metabolic changes, suggesting that metabolism topology reconfiguration may serve as a sensitive imaging biomarker for investigating early CJD pathological changes.

背景：研究脑代谢网络对于理解克雅氏病（CJD）的发病机制和功能改变至关重要。然而，对症状前个体的研究仍然有限。本研究旨在研究PRNP G114V突变无症状携带者的代谢网络拓扑重构。方法：选取来自家族遗传性CJD （gCJD）队列的7例无症状PRNP G114V突变携带者、43例CJD患者和35例健康对照。所有参与者都进行了神经心理学评估、基因检测和18f -氟脱氧葡萄糖正电子发射断层扫描(18F-FDG PET)/MRI扫描。分析无症状PRNP G114V突变携带者与健康对照、CJD患者与对照组之间基于体素的灰质体积和FDG PET标准化摄取值比（SUVRs）。利用图论和稀疏反协方差估计（SICE）评估全脑代谢连接体和拓扑特性。采用空间独立分量分析（ICA）评价子网络，包括默认模式网络（DMN）、显著网络（SN）和中央执行网络（CEN）。结果：就整体特性而言，无症状携带者的协调性显著增加，这与CJD患者的发现一致。我们发现，与健康对照组相比，无症状感染者的右侧前扣带、左侧腹侧前额叶、左侧海马旁回和左侧舌回中心丢失，前额叶中心重构，包括右侧腹内侧前额叶皮层、右侧前额叶前部皮层和右侧眶额中回，这与CJD患者和对照组的比较有重叠。左侧海马旁回局部参数和代谢连通性的改变最为明显。在子网中，无症状载波在SN中表现出更高的分类性和更低的层次性，而DMN和CEN的全局参数没有显著变化。在无症状PRNP携带者中，DMN和SN表现出部分低连通性和超连通性，而CEN主要表现出显著的连通性增强。结论：本研究揭示了无症状PRNP G114V突变携带者的脑代谢拓扑结构和连接组学改变，可在灰质或区域代谢改变之前检测到，提示代谢拓扑重构可作为研究早期CJD病理变化的敏感成像生物标志物。

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引用次数: 0

14-3-3θ phosphorylation exacerbates alpha-synuclein aggregation and toxicity 14-3-3θ磷酸化加剧α -突触核蛋白聚集和毒性。

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease

Pub Date : 2025-01-11 DOI: 10.1016/j.nbd.2025.106801

Bing Wang , Mary Gannon, Rudradip Pattanayak, Kasandra Scholz, Frank Sanders Pair, William J. Stone, Roschongporn Ekkatine, Zhongyu Liu, Talene A. Yacoubian

Aggregation of alpha-synuclein (αsyn) plays an integral role in Parkinson's disease (PD) and Dementia with Lewy bodies (DLB). 14-3-3θ is a highly expressed brain protein with chaperone-like activity that regulates αsyn folding. 14-3-3θ overexpression reduces αsyn aggregation, transmission between cells, and neuronal loss, while 14-3-3 inhibition promotes αsyn pathology. We previously observed increased 14-3-3θ phosphorylation at serine 232 in human PD and DLB brains. Here we examine 14-3-3θ phosphorylation's effects on αsyn aggregation and toxicity. Using a paracrine αsyn model, we found that the non-phosphorylatable S232A 14-3-3θ protected while the phosphomimetic S232D 14-3-3θ failed to protect against αsyn paracrine toxicity. The S232A mutant reduced oligomerization of released αsyn while the S232D mutant did not. The S232D mutant showed significant reduction in αsyn binding compared to wildtype or S232A 14-3-3θ. Using knock-in mouse models expressing the S232A or S232D mutation in the cortex and hippocampus, we examined the impact of S232 phosphorylation on αsyn aggregation in the αsyn preformed fibril (PFF) model. Primary neurons from S232D mice showed increased αsyn inclusion formation compared to neurons from Cre control mice upon PFF treatment. In contrast, neurons from S232A mice showed reduced αsyn inclusions. αSyn PFF injection into the dorsolateral striatum induced higher αsyn inclusion numbers in the sensorimotor cortex of S232D mice compared to Cre control mice. In conclusion, 14-3-3θ phosphorylation at S232 interrupts the ability of 14-3-3θ to bind and regulate αsyn aggregation. Increased 14-3-3θ phosphorylation observed in human PD and DLB likely accelerates neurodegeneration in these disorders.

α -突触核蛋白（αsyn）聚集在帕金森病（PD）和路易体痴呆（DLB）中起着不可或缺的作用。14-3-3θ是一种高表达的脑蛋白，具有伴侣样活性，可调节αsyn折叠。14-3-3θ过表达减少αsyn聚集、细胞间传递和神经元丢失，而14-3-3抑制则促进αsyn病理。我们之前观察到PD和DLB大脑中丝氨酸232的14-3-3θ磷酸化增加。我们研究了14-3-3θ磷酸化对αsyn聚集和毒性的影响。通过旁分泌αsyn模型，我们发现不可磷酸化的S232A 14-3-3θ对αsyn旁分泌毒性具有保护作用，而拟磷的S232D 14-3-3θ对αsyn旁分泌毒性没有保护作用。S232A突变体减少了α - syn释放的寡聚化，而S232D突变体则没有。与野生型或S232A 14-3-3θ相比，S232D突变体αsyn结合显著减少。通过在皮质和海马中表达S232A或S232D突变的敲入小鼠模型，我们研究了S232磷酸化对αsyn预形成纤维（PFF）模型中αsyn聚集的影响。与Cre对照小鼠相比，PFF处理后S232D小鼠的原代神经元αsyn包合物形成增加。相比之下，S232A小鼠的神经元显示αsyn包体减少。将αSyn PFF注射到背外侧纹状体后，S232D小鼠感觉运动皮层αSyn包涵数明显高于Cre对照组。综上所述，14-3-3θ在S232位点的磷酸化阻断了14-3-3θ结合和调节αsyn聚集的能力。在人PD和DLB中观察到的14-3-3θ磷酸化增加可能加速了这些疾病的神经退行性变。

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引用次数: 0