Transient receptor potential vanilloid channel 2 contributes to multi-modal endoplasmic reticulum and perinuclear space dilations that can also be observed in prion-infected mice

瞬时受体电位香草酸亚型2通道导致多模式内质网和核周间隙扩张，这种现象在感染朊病毒的小鼠中也可观察到。

Our recent work on the prion protein and Na+, K+-ATPases (NKAs) led us to revisit data from over 50 years ago, which suggested similarities between vacuolation phenotypes in rodents poisoned with cardiac glycosides (CGs) and spongiform degeneration in prion disease. At that time, this hypothesis was dismissed because the vacuolation observed in prion diseases affects neurons, whereas CG poisoning in rodent brains led to swellings of the endoplasmic reticulum (ER) in astrocytes. We speculated that this difference might be specific to rodents and document here that the vacuolation shifts to neurons in mice expressing a humanized NKA α1 subunit. Next, we investigated the molecular mechanisms that could cause similar ER vacuolation in human cells in vitro. We found that certain stressors-such as overexpression of NKA α subunits and exposure to specific toxins known to trigger the unfolded protein response-can induce a phenotype characterized by profound ER dilation that is most strikingly observed for the perinuclear space (PNS). The ion imbalance typically caused by functional NKAs does not contribute to this phenotype. In fact, it can occur even with the overexpression of catalytically inactive NKAs. Several lines of evidence, generated with pharmacological agents, ion-specific dyes, antagonists, and truncated expression constructs, suggest that a calcium leak channel in the ER, known as transient receptor potential vanilloid 2 (TRPV2), plays a role in this ER and PNS dilation. Additionally, we observed that the formation of these vacuoles coincides with a decrease in steady-state levels of the lipid kinase PIKFYVE, which is recognized for its role in endolysosomal fission and fusion processes. Finally, we found evidence of vacuoles in cryosectioned brains of prion-infected mice that can be filled with a fluorescent marker targeted at the ER and PNS. This raises the possibility that this vacuolation phenomenon contributes to spongiform degeneration seen in prion diseases.

我们最近关于朊蛋白和钠钾 - 腺苷三磷酸酶（NKAs）的研究促使我们重新审视50多年前的数据，这些数据表明，被强心苷（CGs）毒害的啮齿动物的空泡化表型与朊病毒病中的海绵状变性存在相似之处。当时，这一假说被否定了，因为在朊病毒病中观察到的空泡化影响神经元，而啮齿动物大脑中CG中毒会导致星形胶质细胞内质网（ER）肿胀。我们推测这种差异可能是啮齿动物特有的，并在此记录，在表达人源化NKA α1亚基的小鼠中，空泡化会转移到神经元。接下来，我们研究了在体外人细胞中可能导致类似内质网空泡化的分子机制。我们发现，某些应激源，如NKA α亚基的过表达以及暴露于已知会触发未折叠蛋白反应的特定毒素，可诱导一种以内质网深度扩张为特征的表型，这种表型在核周间隙（PNS）最为明显。功能性NKAs通常引起的离子失衡并不会导致这种表型。事实上，即使过表达无催化活性的NKAs也会出现这种情况。通过药理学试剂、离子特异性染料、拮抗剂和截短表达构建体获得的多条证据表明，内质网中一种被称为瞬时受体电位香草酸亚型2（TRPV2）的钙泄漏通道在这种内质网和核周间隙扩张中发挥作用。此外，我们观察到这些空泡的形成与脂质激酶PIKFYVE的稳态水平下降同时发生，已知PIKFYVE在内溶酶体的分裂和融合过程中发挥作用。最后，我们在朊病毒感染小鼠的冰冻切片大脑中发现了空泡的证据，这些空泡可以被靶向内质网和核周间隙的荧光标记物填充。这就提出了一种可能性，即这种空泡化现象可能导致了朊病毒病中所见的海绵状变性。

REF: Zhao W, Eid S, Sackmann C, et al. Transient receptor potential vanilloid channel 2 contributes to multi-modal endoplasmic reticulum and perinuclear space dilations that can also be observed in prion-infected mice. Acta Neuropathol. 2025;149(1):68. Published 2025 Jun 23. doi:10.1007/s00401-025-02906-2 PMID: 40549026

Quantification of Lewy body pathology by cerebrospinal fluid endpoint dilution RT-QuIC in a neuropathological autopsy cohort of clinically heterogeneous participants

在临床异质性参与者的神经病理尸检队列中，通过脑脊液终点稀释实时震动诱导转化技术（RT - QuIC）对路易小体病理进行定量分析

The identification of biomarkers predicting the burden of brain alpha-synuclein (α-syn) pathology in vivo represents a research priority in Lewy body disease (LBD). Recently, some kinetic parameters of seed amplification assays (SAAs) for α-syn showed associations with measures of clinical progression. However, preanalytical and analytical factors significantly affect these parameters, reducing reproducibility. The Endpoint Dilution (ED) SAA Real-time Quaking-induced Conversion (RT-QuIC) is emerging as an alternative, more accurate tool for seed quantification. Still, the approach needs validation in large patient cohorts. We applied the ED RT-QuIC to postmortem ventricular cerebrospinal fluid (CSF) samples from 357 brain donors, including 168 who showed LBD at neuropathologic examination. We estimated the seeding dose, yielding positive responses in 50% of replicate reactions (SD50), using the midSIN algorithm and correlated these values with postmortem synuclein pathology burden and clinical severity measures. LBD was staged through the Unified Staging System for Lewy Body Disorders and the Lewy pathology consensus criteria. The SD50 values (expressed in log10SD/ml) differed significantly among participants at different LBD stages (p < 0.0001), with those at a neocortical stage demonstrating higher values than those at a brainstem-predominant stage (p < 0.0001). The SD50 values were significantly associated with the LBD load evaluated through immunohistochemistry (Rho = 0.62, p < 0.0001). Participants showing higher SD50 values performed worse at the last available scores on clinical scales evaluating motor (Rho = 0.33, p < 0.0001) and olfactory functions (Rho = - 0.33, p < 0.0001). The SD50 scores accurately distinguished neocortical LBD participants from those at lower stages (area under the curve, 0.86; 95% confidence interval, 0.79-0.92). The CSF ED RT-QuIC measure of α-syn seeds correlated significantly with LBD burden and clinical severity scores. These findings validate the CSF ED RT-QuIC as a quantitative assay for misfolded brain α-syn in LBD. This novel approach may be clinically applied to identify individuals at different stages of LBD pathology in research settings.

识别能够在体内预测大脑α-突触核蛋白（α-syn）病理负担的生物标志物是路易体病（LBD）研究的重点。最近，α-syn种子扩增检测（SAAs）的一些动力学参数显示与临床进展指标相关。然而，分析前和分析因素会显著影响这些参数，降低可重复性。终点稀释（ED）实时震动诱导转化（RT - QuIC）种子扩增检测正逐渐成为一种更准确的种子定量替代工具。不过，该方法需要在大规模患者队列中进行验证。我们对357名脑捐赠者的死后心室脑脊液（CSF）样本进行了ED RT - QuIC检测，其中168名在神经病理学检查中显示患有LBD。我们使用midSIN算法估计了在50%的重复反应中产生阳性反应的种子剂量（SD50），并将这些值与死后突触核蛋白病理负担和临床严重程度指标进行了关联分析。通过路易体病统一分期系统和路易体病理共识标准对LBD进行分期。不同LBD分期参与者的SD50值（以log10SD/ml表示）存在显著差异（p < 0.0001），新皮质期患者的SD50值高于脑干为主期患者（p < 0.0001）。SD50值与通过免疫组织化学评估的LBD负荷显著相关（Rho = 0.62，p < 0.0001）。SD50值较高的参与者在评估运动功能（Rho = 0.33，p < 0.0001）和嗅觉功能（Rho = - 0.33，p < 0.0001）的临床量表最后可用评分中表现更差。SD50评分能准确区分新皮质期LBD参与者和较低分期的参与者（曲线下面积为0.86；95%置信区间为0.79 - 0.92）。脑脊液ED RT - QuIC检测的α-syn种子与LBD负担和临床严重程度评分显著相关。这些发现证实了脑脊液ED RT - QuIC可作为一种定量检测LBD中错误折叠脑α-syn的方法。这种新方法在研究环境中可能具有临床应用价值，用于识别处于LBD病理不同阶段的个体。

REF: Mastrangelo A, Caldera S, Mastenbroek SE, et al. Quantification of Lewy body pathology by cerebrospinal fluid endpoint dilution RT-QuIC in a neuropathological autopsy cohort of clinically heterogeneous participants. Acta Neuropathol. 2025;149(1):67. Published 2025 Jun 23. doi:10.1007/s00401-025-02904-4 PMID: 40549179 PMCID: PMC12185638

Role of CSF flow and meningeal barriers in the development of inflammatory lesions at the CNS–PNS transition zone of cranial nerves in autoimmune demyelinating diseases

自身免疫性脱髓鞘疾病中脑脊液流动和脑膜屏障在脑神经中枢神经系统 - 周围神经系统过渡区炎性病灶发展中的作用

Patients with autoimmune inflammatory demyelinating diseases have been shown to present with trigeminal and cochlear nerve lesions restricted at the root transition zone, which contrasts with the relatively extensive distribution of lesions in optic neuritis. To better understand the mechanism underlying the different distribution pattern for cranial nerve lesions in these autoimmune neuroinflammatory diseases, we focused on the CNS-PNS transition zone (TZ) of the trigeminal and cochlear nerves in a MOG-driven active EAE model. These nerves were found to exhibit unique arrangements of anatomical barrier layers including the arachnoid and glia limitans, which affected cerebrospinal fluid (CSF) tracer distribution as well as CCR2+ immune cell infiltration. Our data demonstrated that CCR2+ immune cells accumulate at the TZ on both CNS side and PNS side of the trigeminal nerve and cochlear nerve, which mirror the locations of cranial nerve pathology observed clinically in patients with inflammatory demyelinating disease. On the other hand, the optic and olfactory nerves, which both lack a TZ, did not exhibit restrictions in immune cell localization. Overall, our results reconcile with the hypothesis that the segment of the cranial nerve that is exposed to CSF flow is more susceptible to CCR2+ immune cell infiltration.

已有研究表明，自身免疫性炎性脱髓鞘疾病患者会出现局限于神经根移行区的三叉神经和耳蜗神经损伤，这与视神经炎中损伤相对广泛的分布情况形成对比。为了更好地理解这些自身免疫性神经炎症性疾病中颅神经损伤不同分布模式的潜在机制，我们在髓鞘少突胶质细胞糖蛋白（MOG）驱动的主动实验性自身免疫性脑脊髓炎（EAE）模型中，聚焦于三叉神经和耳蜗神经的中枢神经系统 - 周围神经系统移行区（TZ）。研究发现，这些神经具有独特的解剖屏障层排列，包括蛛网膜和胶质界膜，这会影响脑脊液（CSF）示踪剂的分布以及CCR2 + 免疫细胞的浸润。我们的数据显示，CCR2 + 免疫细胞在三叉神经和耳蜗神经的中枢神经系统侧和周围神经系统侧的移行区积聚，这与临床观察到的炎性脱髓鞘疾病患者颅神经病变的位置相吻合。另一方面，视神经和嗅神经均无移行区，它们在免疫细胞定位方面没有受到限制。总体而言，我们的研究结果支持这样一种假设，即暴露于脑脊液流动的颅神经节段更容易受到CCR2 + 免疫细胞的浸润。

REF: Xin L, Nishihara H, Madarasz A, et al. Role of CSF flow and meningeal barriers in the development of inflammatory lesions at the CNS-PNS transition zone of cranial nerves in autoimmune demyelinating diseases. Acta Neuropathol. 2025;149(1):65. Published 2025 Jun 19. doi:10.1007/s00401-025-02896-1 PMID: 40536593 PMCID: PMC12178981

The olfactory epithelium: a critical gateway for pathological tau propagation and a target for mitigating tauopathy in the central nervous system

嗅觉上皮：病理性tau蛋白传播的关键门户及减轻中枢神经系统tau蛋白病变的靶点

Olfactory impairment is a recognized early indicator of neurodegenerative diseases (NDs), such as Alzheimer's disease (AD). Intracellular aggregates of hyperphosphorylated tau protein, referred to as neurofibrillary tangles (NFTs), are a hallmark of AD. NFTs are found in the olfactory bulb (OB) and entorhinal cortex (EC), both crucial for processing olfactory information. We explored the hypothesis that typical tau lesions could appear early and progress along olfactory regions to reach connected areas critically affected in AD (e.g., EC and hippocampal formation). To that end, we used transgenic PS19 mice expressing mutated human tau protein (1N4R isoform, P301S mutation). The findings also indicate the interest of the OE as a target for intervention aimed at mitigating the progression of tauopathy in the CNS.

嗅觉障碍是公认的神经退行性疾病（NDs）的早期指标，如阿尔茨海默病（AD）。过度磷酸化tau蛋白的细胞内聚集体，即神经原纤维缠结（NFTs），是AD的一个标志。在嗅球（OB）和内嗅皮质（EC）中发现了NFTs，这两个区域对于处理嗅觉信息都至关重要。我们探究了一个假设，即典型的tau病变可能早期出现，并沿着嗅觉区域进展，进而累及在AD中受严重影响的相连区域（如EC和海马结构）。为此，我们使用了表达突变型人类tau蛋白（1N4R亚型，P301S突变）的转基因PS19小鼠。研究结果还表明，将嗅上皮（OE）作为干预靶点以减轻中枢神经系统（CNS）中tau蛋白病变的进展具有一定意义。

REF: Dourte M, Paître E, Bouchoucha M, et al. The olfactory epithelium: a critical gateway for pathological tau propagation and a target for mitigating tauopathy in the central nervous system. Acta Neuropathol. 2025;149(1):64. Published 2025 Jun 19. doi:10.1007/s00401-025-02902-6 PMID: 40536690 PMCID: PMC12179005

Divergent host–pathogen interactions in neurolisteriosis: cytosolic replication vs. phagosomal dormancy of Listeria monocytogenes in CNS macrophages

神经李斯特菌病中不同的宿主 - 病原体相互作用：中枢神经系统巨噬细胞中单核细胞增生李斯特菌的胞质内复制与吞噬体休眠

Bacterial infections of the central nervous system (CNS) pose a significant threat to public health, especially with the growing challenge of antimicrobial resistance. Among these, Listeria monocytogenes (Lm) stands out as a key pathogen, responsible for often fatal neurolisteriosis in humans and cattle. Emerging evidence highlights the distinct roles played by microglia, the resident macrophages of the CNS, and infiltrating monocyte-derived macrophages (MDM) during neuroinflammation. Using bovine models, we investigated the interactions between these two macrophage populations and Lm during infection. Our results show that Lm thrives in the cytosol of microglia, driving productive infection and facilitating bacterial spread. In contrast, MDM effectively sequesters Lm within the phagolysosomal system, limiting its replication and inducing a viable but non-culturable (VBNC) state without completely eliminating the pathogen. Listeriolysin O contributes to the dichotomy of Lm fate, determining whether Lm escapes into the cytosol or transitions to the VBNC state. These findings underscore the complexity of Lm-host dynamics in neurolisteriosis, emphasizing the distinct yet complementary roles of microglia and MDM in shaping CNS infection. By elucidating these mechanisms, our study offers new perspectives on the neurolisteriosis pathogenesis and opens avenues for innovative therapeutic approaches to combat bacterial neuroinfections.

中枢神经系统（CNS）的细菌感染对公众健康构成重大威胁，尤其是在抗菌药物耐药性挑战日益严峻的情况下。在这些细菌中，单核细胞增生李斯特菌（Lm）是一种关键病原体，可导致人类和牛患上常致命的神经李斯特菌病。越来越多的证据表明，中枢神经系统的常驻巨噬细胞——小胶质细胞和浸润的单核细胞衍生巨噬细胞（MDM）在神经炎症过程中发挥着不同的作用。我们利用牛模型研究了这两种巨噬细胞群体与Lm在感染期间的相互作用。我们的研究结果显示，Lm能在小胶质细胞的胞质中大量繁殖，引发有效感染并促进细菌传播。相比之下，MDM能有效地将Lm隔离在吞噬溶酶体系统内，限制其复制并诱导其进入活的但不可培养（VBNC）状态，但无法完全清除病原体。李斯特菌溶血素O导致了Lm不同的命运走向，决定了Lm是逃逸到胞质中还是转变为VBNC状态。这些发现凸显了神经李斯特菌病中Lm与宿主相互作用的复杂性，强调了小胶质细胞和MDM在塑造中枢神经系统感染过程中虽不同但互补的作用。通过阐明这些机制，我们的研究为神经李斯特菌病的发病机制提供了新的视角，并为对抗细菌性神经感染的创新治疗方法开辟了道路。

REF: Tavares-Gomes L, Polidori M, Monney C, et al. Divergent host-pathogen interactions in neurolisteriosis: cytosolic replication vs. phagosomal dormancy of Listeria monocytogenes in CNS macrophages. Acta Neuropathol. 2025;149(1):63. Published 2025 Jun 16. doi:10.1007/s00401-025-02900-8 PMID: 40522474 PMCID: PMC12170700

Characterization of prion strains and peripheral prion infectivity patterns in E200K genetic CJD patients

E200K型遗传性克雅病患者中朊病毒毒株及外周朊病毒感染模式的特征分析

The mutation E200K in the prion protein gene (PRNP) is the most common variant in genetic Creutzfeldt-Jakob disease (gCJD). The clinical and pathological features observed in patients with E200K gCJD led to the hypothesis that the prion strains responsible for this form of the disease may be related to those involved in sporadic CJD (sCJD). In this study, we characterized the prion strains responsible for E200K gCJD cases from Slovakia (n = 12), Spain (n = 9), and France (n = 3) using transgenic mouse models expressing human prion protein (PrP). The cohort included patients with various PRNP genotypes: E200K-Met129/Met129, E200K-Met129/E200K-Met129, E200K-Met129/Val129, and E200K-Val129/Val129. Prion strain characterization revealed that the strains isolated from E200K gCJD cases corresponded to the two most common strains identified in sCJD cases: M1CJD and V2CJD. Depending on the individual, these strains were either present as pure M1CJD or V2CJD, or as a mixture of both (M1CJD + V2CJD). Additionally, peripheral tissues from E200K-Met129/Met129 patients (n = 4) and one E200K-Met129/Val129 case were analyzed for prion infectivity and seeding activity. Similar to sCJD patients, low but detectable levels of prions were found in various peripheral tissues of E200K gCJD cases. Overall, our findings suggest that the prion strains and their distribution in the body are highly similar between E200K gCJD and sCJD patients. These similarities indicate that individuals carrying the E200K mutation may serve as a valuable model for understanding CJD pathogenesis during the preclinical phase of the disease.

朊蛋白基因（PRNP）中的E200K突变是遗传性克雅病（gCJD）中最常见的变异。E200K gCJD患者的临床和病理特征使人们提出假设，即导致这种形式疾病的朊病毒毒株可能与散发性克雅病（sCJD）相关毒株有关。在这项研究中，我们使用表达人类朊蛋白（PrP）的转基因小鼠模型，对来自斯洛伐克（n = 12）、西班牙（n = 9）和法国（n = 3）的E200K gCJD病例的朊病毒毒株进行了表征。该队列包括具有各种PRNP基因型的患者：E200K - Met129/Met129、E200K - Met129/E200K - Met129、E200K - Met129/Val129和E200K - Val129/Val129。朊病毒毒株表征显示，从E200K gCJD病例中分离出的毒株对应于sCJD病例中确定的两种最常见毒株：M1CJD和V2CJD。根据个体情况，这些毒株要么以纯M1CJD或V2CJD形式存在，要么两者混合存在（M1CJD + V2CJD）。此外，对E200K - Met129/Met129患者（n = 4）和1例E200K - Met129/Val129病例的外周组织进行了朊病毒感染性和种子活性分析。与sCJD患者类似，在E200K gCJD病例的各种外周组织中发现了低水平但可检测到的朊病毒。总体而言，我们的研究结果表明，E200K gCJD患者和sCJD患者体内的朊病毒毒株及其分布高度相似。这些相似性表明，携带E200K突变的个体可能是理解疾病临床前期CJD发病机制的有价值模型。

REF: Barrio T, Douet JY, Žáková D, et al. Characterization of prion strains and peripheral prion infectivity patterns in E200K genetic CJD patients. Acta Neuropathol. 2025;149(1):62. Published 2025 Jun 16. doi:10.1007/s00401-025-02903-5 PMID: 40522345 PMCID: PMC12170713

Outcome-associated factors in a molecularly defined cohort of central neurocytoma

分子定义的中枢神经细胞瘤队列中的预后相关因素

Central neurocytomas (CN) are intraventricular brain tumors predominantly occurring in young adults. Although prognosis is usually favorable, tumor recurrence is common, particularly following subtotal resection (STR). Currently, the risk of progression is evaluated using atypical features and an elevated Ki67 proliferation index. However, these markers lack consistent definitions, raising the need for objective criteria. Genome-wide DNA methylation profiles were examined in 136 tumors histologically classified as CN. Clinical/histopathological characteristics were assessed in 93/90 cases, and whole-exome sequencing was conducted in 12 cases. Clinical and molecular characteristics were integrated into a survival model to predict progression-free survival (PFS). A diagnosis of CN was epigenetically confirmed in 125 of 136 cases (92%). No DNA methylation subgroups were identified, but global DNA hypomethylation emerged as a hallmark feature of CN associated with higher recurrence risk. Risk stratification based on histological features of atypia and Ki67 proliferation index was not reproducible across neuropathologists. Hypomethylation at the FGFR3 locus, accompanied by increased FGFR3 protein expression, was observed in 97% of cases. Gross total resection was associated with significantly improved PFS compared to STR, while patients undergoing STR receiving radiotherapy had a better outcome (p = 0.0001). Younger patients were identified as having a higher risk of recurrence (p = 0.026). Patient age and treatment strategy were key factors associated with survival outcomes in this cohort. These findings underscore the importance of closer follow-up for younger patients and radiotherapy for STR cases. Furthermore, FGFR3 represents a hallmark feature and potential therapeutic target, warranting further investigation.

中枢神经细胞瘤（CN）是主要发生于年轻人的脑室内肿瘤。尽管预后通常较好，但肿瘤复发很常见，尤其是在次全切除（STR）后。目前，通过非典型特征和升高的Ki67增殖指数来评估进展风险。然而，这些标志物缺乏统一的定义，因此需要客观的标准。对136例组织学分类为CN的肿瘤进行了全基因组DNA甲基化谱检测。对93/90例患者的临床/组织病理学特征进行了评估，并对12例患者进行了全外显子组测序。将临床和分子特征整合到生存模型中，以预测无进展生存期（PFS）。136例病例中有125例（92%）通过表观遗传学方法确诊为CN。未发现DNA甲基化亚组，但整体DNA低甲基化是CN的一个标志性特征，与更高的复发风险相关。基于非典型组织学特征和Ki67增殖指数进行的风险分层在神经病理学家之间缺乏可重复性。97%的病例观察到成纤维细胞生长因子受体3（FGFR3）基因座低甲基化，同时伴有FGFR3蛋白表达增加。与次全切除相比，肿瘤全切除与显著改善的无进展生存期相关，而接受放疗的次全切除患者预后更好（p = 0.0001）。较年轻的患者被确定为复发风险更高（p = 0.026）。在该队列中，患者年龄和治疗策略是与生存结局相关的关键因素。这些发现强调了对年轻患者进行更密切随访以及对次全切除病例进行放疗的重要性。此外，FGFR3是一个标志性特征和潜在的治疗靶点，值得进一步研究。

REF: Krech M, Muench A, Teichmann D, et al. Outcome-associated factors in a molecularly defined cohort of central neurocytoma. Acta Neuropathol. 2025;149(1):61. Published 2025 Jun 11. doi:10.1007/s00401-025-02894-3 PMID: 40498174 PMCID: PMC12158839

Molecular signatures of regional vulnerability to tauopathy in excitatory cortical neurons

兴奋性皮质神经元中区域对tau蛋白病易感性的分子特征

Tauopathies are characterized by the aggregation and accumulation of hyperphosphorylated tau proteins that correlates with cognitive impairment in affected individuals. The presence of tauopathy follows a temporospatial spreading pattern in which certain neuronal cell types in specific brain regions are more vulnerable to tau accumulation and atrophy. However, the mechanisms underlying the selective vulnerability of these neurons and regions to pathological tau accumulation are not fully understood. Here, we characterized the presence of phosphorylated tau in excitatory and inhibitory neurons in post-mortem prefrontal cortex of tauopathy patients, including Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration, and frontotemporal lobar dementia due to a MAPT mutation. Concordantly, we observed tau-induced changes in spontaneous postsynaptic currents of excitatory neurons in mice especially in the prefrontal cortex. Taken together, we conclude that selective vulnerability to tau could arise from changes in neurotransmission and synaptic compositions, potentially due to an altered Mef2c transcriptional network.

tau蛋白病的特征是过度磷酸化的tau蛋白聚集和积累，这与受影响个体的认知障碍相关。tau蛋白病的发生遵循时空扩散模式，在这种模式中，特定脑区的某些神经元细胞类型更容易发生tau蛋白积累和萎缩。然而，这些神经元和脑区对病理性tau蛋白积累具有选择性易感性的潜在机制尚未完全明确。在此，我们对tau蛋白病患者（包括阿尔茨海默病、进行性核上性麻痹、皮质基底节变性以及由MAPT基因突变导致的额颞叶痴呆）尸检前额叶皮质中兴奋性和抑制性神经元内磷酸化tau蛋白的存在情况进行了分析。一致地，我们观察到在小鼠中，尤其是前额叶皮质的兴奋性神经元的自发突触后电流出现了tau蛋白诱导的变化。综上所述，我们得出结论：对tau蛋白的选择性易感性可能源于神经传递和突触组成的改变，这可能是由于Mef2c转录网络发生了改变。

REF: Broekaart DWM, Sharma A, Ramakrishnan A, et al. Molecular signatures of regional vulnerability to tauopathy in excitatory cortical neurons. Acta Neuropathol. 2025;149(1):60. Published 2025 Jun 7. doi:10.1007/s00401-025-02879-2 PMID: 40481857

Analysis of the splicing landscape of the frontal cortex in FTLD-TDP reveals subtype specific patterns and cryptic splicing

额颞叶痴呆伴TAR DNA结合蛋白43（FTLD - TDP）患者额叶皮质剪接图谱分析揭示了亚型特异性模式和隐蔽剪接

Dysregulation of TDP-43 as seen in TDP-43 proteinopathies leads to specific RNA splicing dysfunction. While discovery studies have explored novel TDP-43-driven splicing events in induced pluripotent stem cell (iPSC)-derived neurons and TDP-43 negative neuronal nuclei, transcriptome-wide investigations in frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP) brains remain unexplored. Such studies hold promise for identifying widespread novel and relevant splicing alterations in FTLD-TDP patient brains. We conducted the largest differential splicing analysis (DSA) using bulk short-read RNAseq data from frontal cortex (FCX) tissue of 127 FTLD-TDP (A, B, C, GRN and C9orf72 carriers) and 22 control subjects (Mayo Clinic Brain Bank), using Leafcutter. Overall, this study provides a comprehensive map of splicing alterations in FTLD-TDP brains, revealing subtype-specific differences and identifying promising candidates for biomarker development and potential common pathogenic mechanisms between FTLD-TDP and AD.

正如在TDP - 43蛋白病中所见，TDP - 43的调节异常会导致特定的RNA剪接功能障碍。虽然探索性研究已在诱导多能干细胞（iPSC）衍生的神经元和TDP - 43阴性神经元细胞核中探索了新型TDP - 43驱动的剪接事件，但在伴有TDP - 43聚集体的额颞叶变性（FTLD - TDP）大脑中进行全转录组研究仍未开展。此类研究有望在FTLD - TDP患者大脑中识别出广泛的新型且相关的剪接改变。我们使用Leafcutter软件，对来自梅奥诊所脑库的127例FTLD - TDP患者（A型、B型、C型、GRN和C9orf72携带者）和22例对照受试者的额叶皮质（FCX）组织的批量短读长RNA测序数据进行了规模最大的差异剪接分析（DSA）。总体而言，本研究提供了FTLD - TDP大脑中剪接改变的综合图谱，揭示了亚型特异性差异，并确定了有潜力用于生物标志物开发的候选指标以及FTLD - TDP和阿尔茨海默病（AD）之间可能存在的共同致病机制。

REF: Faura J, Heeman B, Pottier C, et al. Analysis of the splicing landscape of the frontal cortex in FTLD-TDP reveals subtype specific patterns and cryptic splicing. Acta Neuropathol. 2025;149(1):59. Published 2025 Jun 6. doi:10.1007/s00401-025-02901-7 PMID: 40478310 PMCID: PMC12143990