更新于：2024-11-01

PICALM

更新于：2024-11-01

基本信息

别名

CALM、Clathrin assembly lymphoid myeloid leukemia protein、CLTH

+ [3]

简介

Cytoplasmic adapter protein that plays a critical role in clathrin-mediated endocytosis which is important in processes such as internalization of cell receptors, synaptic transmission or removal of apoptotic cells. Recruits AP-2 and attaches clathrin triskelions to the cytoplasmic side of plasma membrane leading to clathrin-coated vesicles (CCVs) assembly (PubMed:10436022, PubMed:16262731, PubMed:27574975). Furthermore, regulates clathrin-coated vesicle size and maturation by directly sensing and driving membrane curvature (PubMed:25898166). In addition to binding to clathrin, mediates the endocytosis of small R-SNARES (Soluble NSF Attachment Protein REceptors) between plasma membranes and endosomes including VAMP2, VAMP3, VAMP4, VAMP7 or VAMP8 (PubMed:22118466, PubMed:21808019, PubMed:23741335). In turn, PICALM-dependent SNARE endocytosis is required for the formation and maturation of autophagic precursors (PubMed:25241929). Modulates thereby autophagy and the turnover of autophagy substrates such as MAPT/TAU or amyloid precursor protein cleaved C-terminal fragment (APP-CTF) (PubMed:25241929, PubMed:24067654).

关联

项与 PICALM 相关的药物

T-65

靶点

PICALM

作用机制

PICALM stimulators

在研机构-

原研机构

Keck School of Medicine of USC

在研适应症-

非在研适应症

阿尔茨海默症

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PICALM 相关的临床结果

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100 项与 PICALM 相关的转化医学

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0 项与 PICALM 相关的专利（医药）

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375

项与 PICALM 相关的文献（医药）

2024-10-01·Molecular Metabolism

Picalm, a novel regulator of GLUT4-trafficking in adipose tissue

Article

作者: Sehgal, Ratika ; Vogel, Heike ; Jähnert, Markus ; Jonas, Wenke ; Gaugel, Jasmin ; Haacke, Neele ; Hoffmann, Anne ; Schürmann, Annette ; Blüher, Matthias

OBJECTIVEPicalm (phosphatidylinositol-binding clathrin assembly protein), a ubiquitously expressed clathrin-adapter protein, is a well-known susceptibility gene for Alzheimer's disease, but its role in white adipose tissue (WAT) function has not yet been studied. Transcriptome analysis revealed differential expression of Picalm in WAT of diabetes-prone and diabetes-resistant mice, hence we aimed to investigate the potential link between Picalm expression and glucose homeostasis, obesity-related metabolic phenotypes, and its specific role in insulin-regulated GLUT4 trafficking in adipocytes.METHODSPicalm expression and epigenetic regulation by microRNAs (miRNAs) and DNA methylation were analyzed in WAT of diabetes-resistant (DR) and diabetes-prone (DP) female New Zealand Obese (NZO) mice and in male NZO after time-restricted feeding (TRF) and alternate-day fasting (ADF). PICALM expression in human WAT was evaluated in a cross-sectional cohort and assessed before and after weight loss induced by bariatric surgery. siRNA-mediated knockdown of Picalm in 3T3-L1-cells was performed to elucidate functional outcomes on GLUT4-translocation as well as insulin signaling and adipogenesis.RESULTSPicalm expression in WAT was significantly lower in DR compared to DP female mice, as well as in insulin-sensitive vs. resistant NZO males, and was also reduced in NZO males following TRF and ADF. Four miRNAs (let-7c, miR-30c, miR-335, miR-344) were identified as potential mediators of diabetes susceptibility-related differences in Picalm expression, while 11 miRNAs (including miR-23a, miR-29b, and miR-101a) were implicated in TRF and ADF effects. Human PICALM expression in adipose tissue was lower in individuals without obesity vs. with obesity and associated with weight-loss outcomes post-bariatric surgery. siRNA-mediated knockdown of Picalm in mature 3T3-L1-adipocytes resulted in amplified insulin-stimulated translocation of the endogenous glucose transporter GLUT4 to the plasma membrane and increased phosphorylation of Akt and Tbc1d4. Moreover, depleting Picalm before and during 3T3-L1 differentiation significantly suppressed adipogenesis, suggesting that Picalm may have distinct roles in the biology of pre- and mature adipocytes.CONCLUSIONSPicalm is a novel regulator of GLUT4-translocation in WAT, with its expression modulated by both genetic predisposition to diabetes and dietary interventions. These findings suggest a potential role for Picalm in improving glucose homeostasis and highlight its relevance as a therapeutic target for metabolic disorders.

2024-09-01·Human Pathology

Clinicopathologic features and outcomes of acute leukemia harboring PICALM::MLLT10 fusion

Article

作者: Zhang, Xiaohui ; Song, Jinming ; Liu, Yajuan ; He, Rong ; Xu, Xinjie ; Shi, Min ; Wang, Jeffrey ; Chen, Xueyan ; Horna, Pedro ; Herrick, Jennifer L ; Xu, Min ; Yuan, Ji ; Li, Peng ; Buglioni, Alessia ; Zhang, Weiwei ; Jevremovic, Dragan

The PICALM::MLLT10 fusion is a rare but recurrent cytogenetic abnormality in acute leukemia, with limited clinicopathologic and outcome data available. Herein, we analyzed 156 acute leukemia patients with PICALM::MLLT10 fusion, including 12 patients from our institutions and 144 patients from the literature. The PICALM::MLLT10 fusion preferentially manifested in pediatric and young adult patients, with a median age of 24 years. T-lymphoblastic leukemia/lymphoma (T-ALL) constituted 65% of cases, acute myeloid leukemia (AML) 27%, and acute leukemia of ambiguous lineage (ALAL) 8%. About half of T-ALL were classified as an early T-precursor (ETP)-ALL. In our institutions' cohort, mediastinum was the most common extramedullary site of involvement. Eight of 12 patients were diagnosed with T-ALL exhibiting a pro-/pre-T stage phenotype (CD4/CD8-double negative, CD7-positive), and frequent CD79a expression. NGS revealed pathogenic mutations in 5 of 6 tested cases, including NOTCH1, and genes in RAS and JAK-STAT pathways and epigenetic modifiers. Of 138 cases with follow-up, pediatric patients (<18 years) had 5-year overall survival (OS) of 71%, significantly better than adults at 33%. The 5-year OS for AML patients was 25%, notably shorter than T-ALL patients at 54%; this distinction was observed in both pediatric and adult populations. Furthermore, adult but not pediatric ETP-ALL patients demonstrated inferior survival compared to non-ETP-ALL patients. Neither karyotype complexity nor transplant status had a discernible impact on OS. In conclusion, PICALM::MLLT10 fusion is most commonly seen in T-ALL patients, particularly those with an ETP phenotype. AML and adult ETP-ALL patients had adverse prognosis. PICALM::MLTT10 fusion testing should be considered in T-ALL, AML, and ALAL patients.

2024-09-01·Molecular Neurobiology

The Effects of PICALM rs3851179 and Age on Brain Atrophy and Cognition Along the Alzheimer’s Disease Continuum

Article

作者: Liu, Yuanqing ; Chen, Jinhong ; Dai, Hui ; Feng, Mengmeng ; Yang, Yiwen ; Wu, Zhiwei

Rs3851179, a variant of PICALM gene, and age are the risk factors of Alzheimer's disease (AD). AD is divided into early-onset AD (EOAD, < 65 years) and late-onset AD (LOAD, ≥ 65 years) by age. The purpose was to investigate the impact of different genotypes of PICALM rs3851179 on brain atrophy and cognitive decline across the AD continuum in different age groups. Four hundred seven cognitive normal (CN) controls, 362 mild cognitive impairment (MCI) patients, and 94 AD patients were enrolled to assess the interaction between AD continuum, age status, and PICALM on gray matter volume (GMV), global cognition, memory function, and executive function using full factorial ANCOVA (3 × 2 × 2). The interaction between AD continuum and PICALM significantly affected the GMV of the left putamen (PUT.L). rs3851179 A-allele carriers did not show a significant decrease in PUT.L GMV from CN to MCI to AD, while GG-allele carriers did. The interaction between AD continuum and age status was significant on GMV of the left angular gyrus (ANG.L) and right superior occipital gyrus (SOG.R). LOAD had higher GMV of ANG.L and SOG.R than EOAD. The interactive effects among AD continuum, age status, and PICALM were not significant on GMV but were significant on global cognition and executive function. The A-allele was found to have a protective effect on global cognition and executive function in EOAD, but not significantly so in LOAD. PICALM rs3851179 A-allele might alleviate the atrophy of PUT.L across the AD continuum than GG-allele. Age status did not affect the interaction between AD continuum and PICALM on brain atrophy. The ANG.L and SOG.R atrophied more severely in EOAD than in LOAD. Rs3851179 A-allele was protective for global cognition and executive function in EOAD.

项与 PICALM 相关的新闻（医药）

2024-01-18

·奇点网

从脑脊液识出阿尔茨海默病的5个“分身”！

*仅供医学专业人士阅读参考阿尔茨海默病（AD）的病理特征包括大脑中的β-淀粉样蛋白沉积和tau蛋白纤维缠结，即当前药物研发的两个重点方向。就在本月初，仑卡奈单抗在中国获批上市，成为首款在国内上市的治疗阿尔茨海默病的抗Aβ药物。但是越来越多的研究表明，AD的发病机制复杂，具有异质性，如果仅仅集中火力攻于β-淀粉样蛋白沉淀和tau蛋白异常，不同患者的临床获益可能会有很大差异。荷兰阿姆斯特丹自由大学的Betty M. Tijms等人通过对609名参与者的脑脊液进行蛋白质组学分析，揭示5种AD分子亚型。这些亚型分别以神经元增生、先天免疫异常激活、RNA失调、脉络丛功能障碍和血脑屏障功能障碍为特点，具有不同的遗传特征、临床结局、生存时间以及脑皮质萎缩特征[1]。这项研究成果强调了AD个体化治疗的重要性，文章于近日发表在《自然·衰老》期刊上。论文首页脑脊液环绕在大脑和脊髓周围，充当缓冲和保护作用，同时也参与营养物质和废物的运输。位置上的接近，使得脑脊液中的成分变化能够直接反映大脑的健康状况。 2020年，Betty M. Tijms等人基于脑脊液蛋白质组学确定了3种AD分子亚型[2]。如今蛋白质组学技术日益改进，研究者们认为是时候对AD亚型的描述进行完善。此次，他们共获取609名参与者的脑脊液样本。其中419人经生物标志物检测诊断为不同阶段的AD患者，包括认知正常、轻度认知障碍（MCI）、痴呆症；其他人具有正常认知能力且未被诊断为AD。总体来看，有1058种脑脊液蛋白质在非AD患者与AD患者之间差异表达。研究者们进一步采用非负矩阵分解（NMF）的方法来对AD患者进行聚类分析，从而根据脑脊液蛋白质组学特征将AD患者分为5种亚型。 5种亚型的脑脊液蛋白质组学特征亚型1的特点为神经元增生。表达上调的蛋白质与神经元可塑性相关，如突触组装、轴突引导、神经元生成、胶质细胞生成等生理过程。与其相关的AD遗传变异是TREM2 R47H。亚型2的特点为先天免疫异常激活。显示小胶质细胞特异性蛋白水平升高，与先天免疫激活有关。与其相关的AD遗传变异是IDUA、CLNK和SCIMP。亚型3的特点为RNA失调（RNA dysregulation）。表达上调的蛋白质参与细胞骨架组成、轴突运输、蛋白酶体功能、蛋白质折叠，尤其是异质核核糖核蛋白（hnRNP）等RNA结合蛋白，表达明显上调。与其相关的AD遗传变异是BIN1、TREM2 R62H、SPDYE3、SNX1、KAT8。亚型4的特点为脉络丛（产生脑脊液的地方）功能障碍。表达上调的蛋白质中有45%参与脉络丛发育，涉及细胞粘附、SMAD通路；此外还有小胶质细胞等免疫细胞特异性蛋白水平升高。与其相关的AD遗传变异是ABCA7、PICALM、IL-34、CLNK。亚型5的特点为血脑屏障功能障碍。白蛋白、纤维蛋白原、纤溶酶原和凝血酶等本不该存在于大脑的蛋白质，在这类亚型患者的脑脊液中水平异常升高，表明来自血液的蛋白质趁血脑屏障受损渗入大脑；与血液凝固、B细胞介导的免疫反应、急性炎症反应等生理过程相关的蛋白质表达上调。与其相关的AD遗传变异是IL-34、ECHDC3、APP。其中，亚型1、2、3患者的脑脊液tau蛋白水平显著升高，而亚型4、5患者的脑脊液tau蛋白水平大多为正常。相比于对照组，所有AD亚型的APOE e4基因变异水平、AD多基因风险评分（PRS）均更高。亚型5的APOE e4基因变异携带者比例为最高。不同亚型由MCI进展痴呆症的风险不同，亚型2、5的风险最高，亚型4的风险最低。不同亚型的生存情况不同，亚型3患者的平均生存时间最短，为5.6年；亚型1患者的平均生存时间最长，为8.9年。此外，磁共振成像（MRI）扫描结果显示，不同亚型的脑皮质萎缩程度。与亚型1、2、5相比，亚型2、4具有更严重的脑皮质萎缩现象。 5种亚型的MRI图像和临床结局最后，研究者们利用来自欧洲、美国等多个不同国家的多组队列进行验证，通过脑脊液蛋白质组学鉴定其AD亚型。结果观察到，与上面的发现队列中的比例相近，27.9%的AD患者为亚型1，35.5%为亚型2，5.8%为亚型3，17.1%为亚型4，16.6%为亚型5，且特征相符。多国大型队列中验证5种AD亚型这些结果意味着，基于脑脊液确定患者AD亚型或有助于选择个体进行特定的治疗。例如，亚型1的患者可能受益于针对TREM2的治疗，亚型2需要先天免疫抑制剂，亚型3需要恢复RNA功能，亚型4可能从抑制单核细胞浸润中受益，而亚型5需要针对脑血管的治疗[3]。同时，某些治疗产生的副作用也可能取决于亚型。例如在抗体治疗，虽然抗体可能更容易穿过亚型5患者的血脑屏障，但这些人发生脑出血的风险也会增加[3]。总之，提到AD，我们总会下意识将其认定为单一一种疾病进行治疗。而这项研究不仅揭示了AD在分子层面的复杂性，也为AD的个性化医疗提供了新的视角。随着研究的深入，我们有望更好地理解AD的复杂机制，并为患者提供更有效的治疗方案。参考文献：[1]Tijms, B.M., Vromen, E.M., Mjaavatten, O. et al. Cerebrospinal fluid proteomics in patients with Alzheimer’s disease reveals five molecular subtypes with distinct genetic risk profiles. Nat Aging (2024). https://doi.org/10.1038/s43587-023-00550-7[2]Tijms BM, Gobom J, Reus L, Jansen I, Hong S, Dobricic V, Kilpert F, Ten Kate M, Barkhof F, Tsolaki M, Verhey FRJ, Popp J, Martinez-Lage P, Vandenberghe R, Lleó A, Molinuevo JL, Engelborghs S, Bertram L, Lovestone S, Streffer J, Vos S, Bos I; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Blennow K, Scheltens P, Teunissen CE, Zetterberg H, Visser PJ. Pathophysiological subtypes of Alzheimer's disease based on cerebrospinal fluid proteomics. Brain. 2020 Dec 1;143(12):3776-3792. doi: 10.1093/brain/awaa325本文作者丨张艾迪

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