Pub Date : 2025-05-20DOI: 10.1186/s13024-025-00848-7
Min-Young Noh, Seong-il Oh, Young-Eun Kim, Sun Joo Cha, Wonjae Sung, Ki-Wook Oh, Yurim Park, Ji Young Mun, Chang-Seok Ki, Minyeop Nahm, Seung Hyun Kim
Neuronal primary cilia, vital for signaling and cell-cycle regulation, have been implicated in maintaining neuronal identity. While a link between primary ciliary defects and neurodegenerative diseases is emerging, the precise pathological mechanisms remain unclear. We studied the genetic contribution of NEK1 to ALS pathogenesis by analyzing the exome sequences of 920 Korean patients with ALS. To understand the disease contribution of NEK1 variants in ALS, we performed a series of functional studies using patient fibroblasts focusing on primary cilia and microtubule-related phenotypes. In addition, these findings were validated in iPSC-derived motor neurons (iPSC-MNs). NIMA-related kinase 1 (NEK1), a gene encoding a serine/threonine kinase involved in cell cycle regulation, has been identified as a risk gene for amyotrophic lateral sclerosis (ALS). Here, we report that mutations in NEK1 cause primary ciliary abnormality, cell cycle re-entry, and disrupted tubulin acetylation in ALS. We analyzed the whole-exome sequences of 920 Korean patients with sporadic ALS and identified 16 NEK1 variants in 23 patients. We found that two novel variants, p.E853Rfs*9 and p.M1?, reduced NEK1 expression, resulting in loss-of-function (LOF) and one synonymous splicing variant (p.Q132=) exhibited an aberrant isoform lacking exon 5. All three NEK1 variants exhibited abnormal primary ciliary structure, impaired sonic hedgehog signaling, and altered cell-cycle progression. Furthermore, the ALS-linked variants induced intracellular calcium overload followed by Aurora kinase A (AurA)-histone deacetylase (HDAC)6 activation, resulting in ciliary disassembly. These defects were restored by treatment with the intracellular Ca2+ chelator, BAPTA. We also found that NEK1 variants cause decreased α-tubulin acetylation, mitochondrial alteration, and impaired DNA damage response (DDR). Notably, drug treatment to inhibit HDAC6 restored the NEK1-dependent deficits in patient fibroblasts. And, we confirmed that data found in patient fibroblasts were reproduced in iPSC-MNs model. Our results suggest that NEK1 contributes to ALS pathogenesis through the LOF mechanism, and HDAC6 inhibition provides an attractive therapeutic strategy for NEK1 variants associated ALS treatment.
{"title":"Mutations in NEK1 cause ciliary dysfunction as a novel pathogenic mechanism in amyotrophic lateral sclerosis","authors":"Min-Young Noh, Seong-il Oh, Young-Eun Kim, Sun Joo Cha, Wonjae Sung, Ki-Wook Oh, Yurim Park, Ji Young Mun, Chang-Seok Ki, Minyeop Nahm, Seung Hyun Kim","doi":"10.1186/s13024-025-00848-7","DOIUrl":"https://doi.org/10.1186/s13024-025-00848-7","url":null,"abstract":"Neuronal primary cilia, vital for signaling and cell-cycle regulation, have been implicated in maintaining neuronal identity. While a link between primary ciliary defects and neurodegenerative diseases is emerging, the precise pathological mechanisms remain unclear. We studied the genetic contribution of NEK1 to ALS pathogenesis by analyzing the exome sequences of 920 Korean patients with ALS. To understand the disease contribution of NEK1 variants in ALS, we performed a series of functional studies using patient fibroblasts focusing on primary cilia and microtubule-related phenotypes. In addition, these findings were validated in iPSC-derived motor neurons (iPSC-MNs). NIMA-related kinase 1 (NEK1), a gene encoding a serine/threonine kinase involved in cell cycle regulation, has been identified as a risk gene for amyotrophic lateral sclerosis (ALS). Here, we report that mutations in NEK1 cause primary ciliary abnormality, cell cycle re-entry, and disrupted tubulin acetylation in ALS. We analyzed the whole-exome sequences of 920 Korean patients with sporadic ALS and identified 16 NEK1 variants in 23 patients. We found that two novel variants, p.E853Rfs*9 and p.M1?, reduced NEK1 expression, resulting in loss-of-function (LOF) and one synonymous splicing variant (p.Q132=) exhibited an aberrant isoform lacking exon 5. All three NEK1 variants exhibited abnormal primary ciliary structure, impaired sonic hedgehog signaling, and altered cell-cycle progression. Furthermore, the ALS-linked variants induced intracellular calcium overload followed by Aurora kinase A (AurA)-histone deacetylase (HDAC)6 activation, resulting in ciliary disassembly. These defects were restored by treatment with the intracellular Ca2+ chelator, BAPTA. We also found that NEK1 variants cause decreased α-tubulin acetylation, mitochondrial alteration, and impaired DNA damage response (DDR). Notably, drug treatment to inhibit HDAC6 restored the NEK1-dependent deficits in patient fibroblasts. And, we confirmed that data found in patient fibroblasts were reproduced in iPSC-MNs model. Our results suggest that NEK1 contributes to ALS pathogenesis through the LOF mechanism, and HDAC6 inhibition provides an attractive therapeutic strategy for NEK1 variants associated ALS treatment.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"18 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144097341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-15DOI: 10.1186/s13024-025-00838-9
Adam N. Trautwig, Edward J. Fox, Eric B. Dammer, Anantharaman Shantaraman, Lingyan Ping, Duc M. Duong, Caroline M. Watson, Fang Wu, Seneshaw Asress, Qi Guo, Allan I. Levey, James J. Lah, Federico Verde, Alberto Doretti, Antonia Ratti, Nicola Ticozzi, Cindy V. Ly, Timothy M. Miller, Mark A. Garret, James D. Berry, Eleanor V. Thomas, Christina N. Fournier, Zachary T. McEachin, Nicholas T. Seyfried, Jonathan D. Glass
Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease involving loss of motor neurons, typically results in death within 3–5 years of disease onset. Although roughly 10% of cases can be linked to a specific inherited mutation (e.g., C9orf72 hexanucleotide repeat expansion or SOD1 mutation), the cause(s) of most cases are unknown. Consequently, there is a critical need for biomarkers that reflect disease onset and progression across ALS subgroups. We employed tandem mass tag mass spectrometry (TMT-MS) based proteomics on cerebrospinal fluid (CSF) to identify and quantify 2105 proteins from sporadic, C9orf72, and SOD1 ALS patients, asymptomatic C9orf72 expansion carriers, and controls (N = 101). To verify trends in our Emory University cohort we used data-independent acquisition (DIA-MS) on an expanded, four center cohort. This expanded cohort of 259 individuals included 50 sporadic ALS (sALS), 43 C9orf72 ALS, 22 SOD1 ALS, 72 asymptomatic gene carriers (59 C9orf72 and 13 SOD1) and 72 age-matched controls. We identified 2330 proteins and used differential protein abundance and network analyses to determine how protein profiles vary across disease subtypes in ALS CSF. Differential abundance and co-expression network analysis identified proteomic differences between ALS and control, as well as differentially abundant proteins between sporadic, C9orf72 and SOD1 ALS. A panel of proteins differentiated forms of ALS that are indistinguishable in a clinical setting. An additional panel differentiated asymptomatic from symptomatic C9orf72 and SOD1 mutation carriers, marking a pre-symptomatic proteomic signature of genetic forms of ALS. Leveraging this large, multicenter cohort, we validated our ALS CSF network and identified ALS-specific proteins and network modules. This study represents a comprehensive analysis of the CSF proteome across sporadic and genetic causes of ALS that resolves differences among these ALS subgroups and also identifies proteins that distinguish symptomatic from asymptomatic gene carriers. These new data point to varying pathogenic pathways that result in an otherwise clinically indistinguishable disease.
{"title":"Network analysis of the cerebrospinal fluid proteome reveals shared and unique differences between sporadic and familial forms of amyotrophic lateral sclerosis","authors":"Adam N. Trautwig, Edward J. Fox, Eric B. Dammer, Anantharaman Shantaraman, Lingyan Ping, Duc M. Duong, Caroline M. Watson, Fang Wu, Seneshaw Asress, Qi Guo, Allan I. Levey, James J. Lah, Federico Verde, Alberto Doretti, Antonia Ratti, Nicola Ticozzi, Cindy V. Ly, Timothy M. Miller, Mark A. Garret, James D. Berry, Eleanor V. Thomas, Christina N. Fournier, Zachary T. McEachin, Nicholas T. Seyfried, Jonathan D. Glass","doi":"10.1186/s13024-025-00838-9","DOIUrl":"https://doi.org/10.1186/s13024-025-00838-9","url":null,"abstract":"Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease involving loss of motor neurons, typically results in death within 3–5 years of disease onset. Although roughly 10% of cases can be linked to a specific inherited mutation (e.g., C9orf72 hexanucleotide repeat expansion or SOD1 mutation), the cause(s) of most cases are unknown. Consequently, there is a critical need for biomarkers that reflect disease onset and progression across ALS subgroups. We employed tandem mass tag mass spectrometry (TMT-MS) based proteomics on cerebrospinal fluid (CSF) to identify and quantify 2105 proteins from sporadic, C9orf72, and SOD1 ALS patients, asymptomatic C9orf72 expansion carriers, and controls (N = 101). To verify trends in our Emory University cohort we used data-independent acquisition (DIA-MS) on an expanded, four center cohort. This expanded cohort of 259 individuals included 50 sporadic ALS (sALS), 43 C9orf72 ALS, 22 SOD1 ALS, 72 asymptomatic gene carriers (59 C9orf72 and 13 SOD1) and 72 age-matched controls. We identified 2330 proteins and used differential protein abundance and network analyses to determine how protein profiles vary across disease subtypes in ALS CSF. Differential abundance and co-expression network analysis identified proteomic differences between ALS and control, as well as differentially abundant proteins between sporadic, C9orf72 and SOD1 ALS. A panel of proteins differentiated forms of ALS that are indistinguishable in a clinical setting. An additional panel differentiated asymptomatic from symptomatic C9orf72 and SOD1 mutation carriers, marking a pre-symptomatic proteomic signature of genetic forms of ALS. Leveraging this large, multicenter cohort, we validated our ALS CSF network and identified ALS-specific proteins and network modules. This study represents a comprehensive analysis of the CSF proteome across sporadic and genetic causes of ALS that resolves differences among these ALS subgroups and also identifies proteins that distinguish symptomatic from asymptomatic gene carriers. These new data point to varying pathogenic pathways that result in an otherwise clinically indistinguishable disease.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"4 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143979449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-13DOI: 10.1186/s13024-025-00836-x
Philip Pikus, R. Scott Turner, G. William Rebeck
The development of anti-amyloid-beta (Aβ) immunotherapies as the first disease modifying therapy for Alzheimer’s Disease (AD) is a breakthrough of basic research and translational science. Genetically modified mouse models developed to study AD neuropathology and physiology were used for the discovery of Aβ immunotherapies and helped ultimately propel therapies to FDA approval. Nonetheless, the combination of modest efficacy and significant rates of an adverse side effect (amyloid related imaging abnormalities, ARIA), has prompted reverse translational research in these same mouse models to better understand the mechanism of the therapies. This review considers the use of these mouse models in understanding the mechanisms of Aβ clearance, cerebral amyloid angiopathy (CAA), blood brain barrier breakdown, neuroinflammation, and neuronal dysfunction in response to Aβ immunotherapy.
抗淀粉样蛋白- β (a β)免疫疗法的发展作为阿尔茨海默病（AD）的第一个疾病修饰疗法是基础研究和转化科学的突破。用于研究阿尔茨海默病神经病理学和生理学的转基因小鼠模型被用于发现Aβ免疫疗法，并最终帮助推动疗法获得FDA的批准。尽管如此，适度的疗效和显著的不良副作用（淀粉样蛋白相关成像异常，ARIA）的结合，促使在这些相同的小鼠模型中进行反向转化研究，以更好地了解治疗的机制。这篇综述考虑了使用这些小鼠模型来理解Aβ清除、脑淀粉样血管病（CAA）、血脑屏障破坏、神经炎症和神经元功能障碍对Aβ免疫治疗的反应机制。
{"title":"Mouse models of Anti-Aβ immunotherapies","authors":"Philip Pikus, R. Scott Turner, G. William Rebeck","doi":"10.1186/s13024-025-00836-x","DOIUrl":"https://doi.org/10.1186/s13024-025-00836-x","url":null,"abstract":"The development of anti-amyloid-beta (Aβ) immunotherapies as the first disease modifying therapy for Alzheimer’s Disease (AD) is a breakthrough of basic research and translational science. Genetically modified mouse models developed to study AD neuropathology and physiology were used for the discovery of Aβ immunotherapies and helped ultimately propel therapies to FDA approval. Nonetheless, the combination of modest efficacy and significant rates of an adverse side effect (amyloid related imaging abnormalities, ARIA), has prompted reverse translational research in these same mouse models to better understand the mechanism of the therapies. This review considers the use of these mouse models in understanding the mechanisms of Aβ clearance, cerebral amyloid angiopathy (CAA), blood brain barrier breakdown, neuroinflammation, and neuronal dysfunction in response to Aβ immunotherapy.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"38 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143939765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-10DOI: 10.1186/s13024-025-00842-z
Neil Donison, Jacqueline Palik, Kathryn Volkening, Michael J. Strong
Tau protein plays a critical role in the physiological functioning of the central nervous system by providing structural integrity to the cytoskeletal architecture of neurons and glia through microtubule assembly and stabilization. Under certain pathological conditions, tau is aberrantly phosphorylated and aggregates into neurotoxic fibrillary tangles. The aggregation and cell-to-cell propagation of pathological tau leads to the progressive deterioration of the nervous system. The clinical entity of traumatic brain injury (TBI) ranges from mild to severe and can promote tau aggregation by inducing cellular mechanisms and signalling pathways that increase tau phosphorylation and aggregation. Chronic traumatic encephalopathy (CTE), which is a consequence of repetitive TBI, is a unique tauopathy characterized by pathological tau aggregates located at the depths of the sulci and surrounding blood vessels. The mechanisms leading to increased tau phosphorylation and aggregation in CTE remain to be fully defined but are likely the result of the primary and secondary injury sequelae associated with TBI. The primary injury includes physical and mechanical damage resulting from the head impact and accompanying forces that cause blood–brain barrier disruption and axonal shearing, which primes the central nervous system to be more vulnerable to the subsequent secondary injury mechanisms. A complex interplay of neuroinflammation, oxidative stress, excitotoxicity, and mitochondrial dysfunction activate kinase and cell death pathways, increasing tau phosphorylation, aggregation and neurodegeneration. In this review, we explore the most recent insights into the mechanisms of tau phosphorylation associated with TBI and propose how multiple cellular pathways converge on tau phosphorylation, which may contribute to CTE progression.
{"title":"Cellular and molecular mechanisms of pathological tau phosphorylation in traumatic brain injury: implications for chronic traumatic encephalopathy","authors":"Neil Donison, Jacqueline Palik, Kathryn Volkening, Michael J. Strong","doi":"10.1186/s13024-025-00842-z","DOIUrl":"https://doi.org/10.1186/s13024-025-00842-z","url":null,"abstract":"Tau protein plays a critical role in the physiological functioning of the central nervous system by providing structural integrity to the cytoskeletal architecture of neurons and glia through microtubule assembly and stabilization. Under certain pathological conditions, tau is aberrantly phosphorylated and aggregates into neurotoxic fibrillary tangles. The aggregation and cell-to-cell propagation of pathological tau leads to the progressive deterioration of the nervous system. The clinical entity of traumatic brain injury (TBI) ranges from mild to severe and can promote tau aggregation by inducing cellular mechanisms and signalling pathways that increase tau phosphorylation and aggregation. Chronic traumatic encephalopathy (CTE), which is a consequence of repetitive TBI, is a unique tauopathy characterized by pathological tau aggregates located at the depths of the sulci and surrounding blood vessels. The mechanisms leading to increased tau phosphorylation and aggregation in CTE remain to be fully defined but are likely the result of the primary and secondary injury sequelae associated with TBI. The primary injury includes physical and mechanical damage resulting from the head impact and accompanying forces that cause blood–brain barrier disruption and axonal shearing, which primes the central nervous system to be more vulnerable to the subsequent secondary injury mechanisms. A complex interplay of neuroinflammation, oxidative stress, excitotoxicity, and mitochondrial dysfunction activate kinase and cell death pathways, increasing tau phosphorylation, aggregation and neurodegeneration. In this review, we explore the most recent insights into the mechanisms of tau phosphorylation associated with TBI and propose how multiple cellular pathways converge on tau phosphorylation, which may contribute to CTE progression. ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"36 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143930936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-09DOI: 10.1186/s13024-025-00847-8
John Hardy, Patrick Lewis
While APP is largely neuonally expressed, Aβ amyloid is largely produced by microglia as the clearance mechanisms for damaged membranes becomes overwhelmed.
{"title":"Evidence suggesting that microglia make amyloid from neuronally expressed APP: a hypothesis","authors":"John Hardy, Patrick Lewis","doi":"10.1186/s13024-025-00847-8","DOIUrl":"https://doi.org/10.1186/s13024-025-00847-8","url":null,"abstract":"While APP is largely neuonally expressed, Aβ amyloid is largely produced by microglia as the clearance mechanisms for damaged membranes becomes overwhelmed.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"74 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-09DOI: 10.1186/s13024-025-00846-9
Wongu Youn, Mijin Yun, C. Justin Lee, Michael Schöll
In the recent decade, there has been a surge of efforts to develop scalable, specific and cost-effective biomarkers in blood to diagnose neurodegenerative diseases and prognose their progress even before overt symptoms manifest. Among an array of brain-associated proteins, glial fibrillary acidic protein (GFAP) has emerged as a compelling biomarker candidate, often in conjunction with other biomarkers. GFAP levels in bodily fluid, especially blood and cerebrospinal fluid (CSF), have underscored associations with disease progression by robust support in a substantial body of reports encompassing cohorts afflicted with a spectrum of brain and spinal cord disorders, including progressive neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease, multiple sclerosis and Lewy body dementia. Notably, GFAP in CSF is known to reflect astrogliosis in alignment with other astrogliosis marker levels such as S100β, chitinase-3-like protein 1 (CHI3L1, also known as YKL40 in humans and BMP39 in mice), aquaporin 4, evidence in tissue by immunohistochemistry staining, and uptake of certain PET radiotracers targeting reactive astrocytes, i.e., 11C-deuterium-L-deprenyl (11C-DED), 11C-BU99008, 11C-SMBT-1 or 11 C-acetate [1]. On the other hand, GFAP levels in blood seem to demonstrate more precise diagnostic performance than CSF GFAP level in an AD context. Patient case studies employing MRI and PET have underscored correlations between disease progression and GFAP levels in bodily fluids, with plasma GFAP yielding greater significance [2]. Furthermore, recent cohort studies suggest that the effect of amyloid-β (Aβ) on tau pathology may be modulated by astrocytic reactivity, which was suggested to be indicated by increased plasma GFAP levels [3]. The recent inclusion of interchangeable use of plasma and CSF GFAP as a marker of inflammation (category ‘I’) in the Alzheimer’s Association Workgroup criteria for diagnosis and staging of Alzheimer’s disease showcases its suggested diagnostic potential [4]. We argue, however, that there are several concerns regarding the use of blood GFAP as a direct biomarker for astrocyte reactivity. Research has identified discrepancies between astrocyte reactivity examined by 11C-deuterium-L-deprenyl (11C-DED) PET imaging and plasma GFAP levels in AD patients [5], with more significant changes observed in blood GFAP levels than in cerebrospinal fluid (CSF) GFAP levels [6]. In this perspective, we argue that astrocytic reactivity cannot be represented solely from blood GFAP level, and more direct methods for examining astrocyte reactivity such as PET imaging must be followed. Our argument is based on two primary concerns: the ambiguous origin of plasma GFAP and inconsistencies between blood GFAP level increases and other biomarkers.
First, the origin of blood GFAP remains unclear, with uncertainty about whether plasma GFAP derives
这种时间和空间上的差异使人们对血液GFAP与星形细胞反应性的直接联系产生了疑问。脑脊液和血浆GFAP水平之间的差异并不是唯一的疑点；GFAP在各种体细胞中的表达也提出了关于血液GFAP真正起源的问题。尽管GFAP被广泛认为是星形细胞特异性蛋白，但其作用仍然知之甚少，部分原因是其在不同脑细胞类型和星形细胞亚群中的表达变化。即使在人脑中，也存在其他表达gfap的细胞，如发育中的神经祖细胞和室管膜细胞，需要钙结合蛋白B （S100β）、兴奋性氨基酸转运蛋白1 （EAAT1或GLAST）、谷氨酰胺合成酶（GS）和醛脱氢酶1家族成员L1 （ALDH1L1）等补充标记物来准确识别星形胶质细胞。除中枢神经系统外，正常情况下，GFAP在外周神经系统（PNS）的非髓鞘雪旺细胞、视网膜的神经胶质、肠神经系统（ENS）的肠胶质细胞、肾小管细胞、睾丸的Leydig和Sertoli细胞以及肝脏、皮肤、骨骼和胎盘的各种细胞类型中也有表达[7]。值得注意的是，在病理状态下，这些非脑GFAP表达细胞也上调GFAP，使查明血液GFAP起源的尝试复杂化。例如，GFAP在炎症性肠病患者的肠道中过度表达；帕金森病与肠胶质细胞GFAP表达和磷酸化升高有关；肝星状细胞在肝纤维化区附近显示GFAP过表达；在复杂胸主动脉手术后的血流中检测到GFAP。尽管有这些观察结果，还没有直接证据表明血液GFAP起源于大脑中的反应性星形胶质细胞。其次，血浆GFAP水平与其他神经胶质生物标志物之间的相关性不一致，而脑脊液GFAP水平与这些标志物密切相关。胶质生物标志物不仅仅局限于GFAP，还包括反应性星形胶质细胞的不同标志物，如CHI3L1和S100B，以及小胶质细胞分泌的髓样细胞2上表达的可溶性触发受体（sTREM2）。虽然脑脊液GFAP水平与这些胶质生物标志物相关，但通过不同的PET示踪剂或尸检研究，关于血浆GFAP水平与星形胶质细胞形成的相关性存在矛盾的报道。因此，与对照组相比，散发性AD患者血浆GFAP水平与18F-SMBT-1摄取[11]呈正相关，但与11C-DED[5]或脑组织GFAP水平[8]无相关性，甚至呈负相关，提示反应性星形胶质细胞或脑脊液释放之外的机制可能导致血液GFAP水平[6]升高。此外，在一项多发性硬化症（MS）的队列研究中，血清GFAP水平无法预测疾病的活动性和进展，而CSF GFAP水平是显著的预测因子，尽管CSF和血清GFAP水平与其他胶质/神经炎症标志物[12]存在相关性。深入到更实际的考虑，定量血液中GFAP水平对传统的ELISA方法来说是一个挑战，这导致了采用超灵敏技术，如SIMOA。然而，研究中GFAP水平的不一致性表明其作为生物标志物的使用缺乏标准化的标准，这可能是由于基于抗体的方法的局限性，包括聚集相关的钩效应和多种GFAP亚型和翻译后修饰[13]的存在。为了使GFAP成为更可靠的生物标志物，标准化的定量方法、包含抗体信息的样品处理方案以及对GFAP同种异构体的全面研究对于阐明GFAP释放的起源和提高其分析准确性至关重要。尽管血液GFAP水平升高有许多限制和未解决的问题，但这些水平仍然被广泛接受为反映神经退行性疾病阶段的生物标志物，不仅针对AD，还针对早期淀粉样变，痴呆或更快的认知能力下降bb0。与其他标志物如磷酸化的tau蛋白、β 42/40淀粉样蛋白和神经丝轻链蛋白（NfL）一起，血液GFAP被认为可以增强我们对疾病进展的理解。然而，要使GFAP被认为是一种可靠的生物标志物，对其起源及其与病理生理条件的因果关系进行严格的检查是必不可少的，要以具体的生物学证据为基础，而不仅仅是相关性。 为了真正确定GFAP的价值，我们必须进行全面的研究，包括绘制GFAP在所有相关组织中的表达图谱，选择性地标记或靶向特定细胞类型中的GFAP，例如，与针对特定细胞的PET成像一起，并密切检查触发星形胶质细胞和反应性星形胶质细胞释放GFAP的条件。观察GFAP释放的一种方法可能是通过星形胶质细胞特异性标记分析星形胶质细胞衍生的外泌体。这些生物学分析必须得到全球纵向队列研究的支持，这些研究采用严格标准化的测量方法，以及反应性星形胶质细胞成像探针的支持。只有通过这种彻底和细致的方法，我们才能超越表面的联系，利用GFAP作为神经退行性疾病中星形胶质细胞反应的精确、可靠的生物标志物。不适用。该研究包含来自已发表研究的公开数据。李俊华，李俊杰，尹明。阿尔茨海默病的一个关键介质和成像靶点：通过MAOB解锁反应性星形胶质细胞增生的作用。中华医学杂志，2009;38(5):397 - 397。[文章]学者沈晓宁，黄世勇，崔敏，赵启华，郭勇，黄永勇，张伟，马永华，陈绍东，张永荣，等。阿尔茨海默病连续体中的血浆胶质原纤维酸性蛋白：与其他生物标志物、鉴别诊断和临床进展预测的关系中国生物医学工程学报（英文版）；2009;36(4):411 - 421。[文章]学者Bellaver B， Povala G, Ferreira PCL, jo<e:1> o PF-S, Leffa DT, Lussier FZ, Benedet AL, Ashton NJ, Triana-Baltzer G, Kolb HC，等。星形胶质细胞反应性影响淀粉样蛋白β对临床前阿尔茨海默病Tau病理的影响。中华医学杂志，2009;29:1774-81。[10]刘建军，刘建军，刘建军，刘建军，等。阿尔茨海默病诊断和分期的修订标准：阿尔茨海默病协会工作组。阿尔茨海默病。2024;20(8):5143-69。[j]学者Chiotis K， Johansson C, Rodriguez-Vieitez E, Ashton NJ, Blennow K, Zetterberg H, Graff C, Nordberg A.多模态PET和血浆GFAP追踪常染色体遗传和散发性阿尔茨海默病反应性星形胶质细胞增生。神经退行性疾病杂志。2023;18:60。文章学者Benedet AL， Milà-Alomà M, Vrillon A, Ashton NJ, Pascoal TA, Lussier F, Karikari TK, Hourregue C, Cognat Emmanuel, Dumurgier J，等。血浆和脑脊液胶质纤维酸性蛋白水平在阿尔茨海默病连续体中的差异中华神经科杂志，2011;38(12):1471 - 1483。文章发表于PubMed bbb学者Messing A， Brenner M. GFAP 50岁。神经网络学报，2020;0:1-23。[10]学者Varma VR， An Y, Kac PR, Bilgel M, Moghekar A, Loeffler T, Amschl D, Troncoso J, Blennow K, Zetterberg H，等。血液生物标志物的纵向进展揭示了星形胶质细胞反应性在临床前阿尔茨海默病中的关键作用。MedRxiv。2024. https://doi.org/10.1101/2024.01.25.24301779.Article PubMed PubMed Central bbb学者Peretti DE， Bocca
{"title":"Cautions on utilizing plasma GFAP level as a biomarker for reactive astrocytes in neurodegenerative diseases","authors":"Wongu Youn, Mijin Yun, C. Justin Lee, Michael Schöll","doi":"10.1186/s13024-025-00846-9","DOIUrl":"https://doi.org/10.1186/s13024-025-00846-9","url":null,"abstract":"<p>In the recent decade, there has been a surge of efforts to develop scalable, specific and cost-effective biomarkers in blood to diagnose neurodegenerative diseases and prognose their progress even before overt symptoms manifest. Among an array of brain-associated proteins, glial fibrillary acidic protein (GFAP) has emerged as a compelling biomarker candidate, often in conjunction with other biomarkers. GFAP levels in bodily fluid, especially blood and cerebrospinal fluid (CSF), have underscored associations with disease progression by robust support in a substantial body of reports encompassing cohorts afflicted with a spectrum of brain and spinal cord disorders, including progressive neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease, multiple sclerosis and Lewy body dementia. Notably, GFAP in CSF is known to reflect astrogliosis in alignment with other astrogliosis marker levels such as S100β, chitinase-3-like protein 1 (CHI3L1, also known as YKL40 in humans and BMP39 in mice), aquaporin 4, evidence in tissue by immunohistochemistry staining, and uptake of certain PET radiotracers targeting reactive astrocytes, i.e., <sup>11</sup>C-deuterium-L-deprenyl (<sup>11</sup>C-DED), <sup>11</sup>C-BU99008, <sup>11</sup>C-SMBT-1 or <sup>11</sup> C-acetate [1]. On the other hand, GFAP levels in blood seem to demonstrate more precise diagnostic performance than CSF GFAP level in an AD context. Patient case studies employing MRI and PET have underscored correlations between disease progression and GFAP levels in bodily fluids, with plasma GFAP yielding greater significance [2]. Furthermore, recent cohort studies suggest that the effect of amyloid-β (Aβ) on tau pathology may be modulated by astrocytic reactivity, which was suggested to be indicated by increased plasma GFAP levels [3]. The recent inclusion of interchangeable use of plasma and CSF GFAP as a marker of inflammation (category ‘I’) in the Alzheimer’s Association Workgroup criteria for diagnosis and staging of Alzheimer’s disease showcases its suggested diagnostic potential [4]. We argue, however, that there are several concerns regarding the use of blood GFAP as a direct biomarker for astrocyte reactivity. Research has identified discrepancies between astrocyte reactivity examined by <sup>11</sup>C-deuterium-L-deprenyl (<sup>11</sup>C-DED) PET imaging and plasma GFAP levels in AD patients [5], with more significant changes observed in blood GFAP levels than in cerebrospinal fluid (CSF) GFAP levels [6]. In this perspective, we argue that astrocytic reactivity cannot be represented solely from blood GFAP level, and more direct methods for examining astrocyte reactivity such as PET imaging must be followed. Our argument is based on two primary concerns: the ambiguous origin of plasma GFAP and inconsistencies between blood GFAP level increases and other biomarkers.</p><p>First, the origin of blood GFAP remains unclear, with uncertainty about whether plasma GFAP derives","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"49 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-08DOI: 10.1186/s13024-025-00839-8
Elise A. Kellett, Adekunle T. Bademosi, Adam K. Walker
Increased phosphorylation of TDP-43 is a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the regulation and roles of TDP-43 phosphorylation remain incompletely understood. A variety of techniques have been utilized to understand TDP-43 phosphorylation, including kinase/phosphatase manipulation, phosphomimic variants, and genetic, physical, or chemical inducement in a variety of cell cultures and animal models, and via analyses of post-mortem human tissues. These studies have produced conflicting results: suggesting incongruously that TDP-43 phosphorylation may either drive disease progression or serve a neuroprotective role. In this review, we explore the roles of regulators of TDP-43 phosphorylation including the putative TDP-43 kinases c-Abl, CDC7, CK1, CK2, IKKβ, p38α/MAPK14, MEK1, TTBK1, and TTBK2, and TDP-43 phosphatases PP1, PP2A, and PP2B, in disease. Building on recent studies, we also examine the consequences of TDP-43 phosphorylation on TDP-43 pathology, especially related to TDP-43 mislocalisation, liquid–liquid phase separation, aggregation, and neurotoxicity. By comparing conflicting findings from various techniques and models, this review highlights both the discrepancies and unresolved aspects in the understanding of TDP-43 phosphorylation. We propose that the role of TDP-43 phosphorylation is site and context dependent, and includes regulation of liquid–liquid phase separation, subcellular mislocalisation, and degradation. We further suggest that greater consideration of the normal functions of the regulators of TDP-43 phosphorylation that may be perturbed in disease is warranted. This synthesis aims to build towards a comprehensive understanding of the complex role of TDP-43 phosphorylation in the pathogenesis of neurodegeneration. TDP-43 is subject to phosphorylation by kinases and dephosphorylation by phosphatases, which variably impacts protein localisation, aggregation, and neurotoxicity in neurodegenerative diseases.
{"title":"Molecular mechanisms and consequences of TDP-43 phosphorylation in neurodegeneration","authors":"Elise A. Kellett, Adekunle T. Bademosi, Adam K. Walker","doi":"10.1186/s13024-025-00839-8","DOIUrl":"https://doi.org/10.1186/s13024-025-00839-8","url":null,"abstract":"Increased phosphorylation of TDP-43 is a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the regulation and roles of TDP-43 phosphorylation remain incompletely understood. A variety of techniques have been utilized to understand TDP-43 phosphorylation, including kinase/phosphatase manipulation, phosphomimic variants, and genetic, physical, or chemical inducement in a variety of cell cultures and animal models, and via analyses of post-mortem human tissues. These studies have produced conflicting results: suggesting incongruously that TDP-43 phosphorylation may either drive disease progression or serve a neuroprotective role. In this review, we explore the roles of regulators of TDP-43 phosphorylation including the putative TDP-43 kinases c-Abl, CDC7, CK1, CK2, IKKβ, p38α/MAPK14, MEK1, TTBK1, and TTBK2, and TDP-43 phosphatases PP1, PP2A, and PP2B, in disease. Building on recent studies, we also examine the consequences of TDP-43 phosphorylation on TDP-43 pathology, especially related to TDP-43 mislocalisation, liquid–liquid phase separation, aggregation, and neurotoxicity. By comparing conflicting findings from various techniques and models, this review highlights both the discrepancies and unresolved aspects in the understanding of TDP-43 phosphorylation. We propose that the role of TDP-43 phosphorylation is site and context dependent, and includes regulation of liquid–liquid phase separation, subcellular mislocalisation, and degradation. We further suggest that greater consideration of the normal functions of the regulators of TDP-43 phosphorylation that may be perturbed in disease is warranted. This synthesis aims to build towards a comprehensive understanding of the complex role of TDP-43 phosphorylation in the pathogenesis of neurodegeneration. TDP-43 is subject to phosphorylation by kinases and dephosphorylation by phosphatases, which variably impacts protein localisation, aggregation, and neurotoxicity in neurodegenerative diseases. ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"74 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143920371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUNDWhile the temporal profile of amyloid (Aβ) and tau cerebrospinal fluid (CSF) biomarkers along the Alzheimer's disease (AD) continuum is well-studied, chronological changes of CSF proteins reflecting other disease-relevant processes, denoted 'X' in the ATX(N) framework, remain poorly understood.METHODSUsing an untargeted mass spectrometric approach termed tandem mass tag (TMT), we quantified over 1500 CSF proteins across the AD continuum in three independent cohorts, finely staged by Aβ/tau positron emission tomography (PET), fluid biomarkers, or brain biopsy. Weighted protein co-expression network analysis identified clusters of proteins robustly correlating in all three cohorts which sequentially changed with AD progression. Obtained protein clusters were correlated with fluid biomarker measurements (phosphorylated tau (p-tau) species including p-tau181, p-tau217, and p-tau205, as well as Aβ), Aβ/tau PET imaging, and clinical parameters to discern disease-relevant clusters which were modelled across the AD continuum.RESULTSNeurodegeneration-related proteins (e.g., 14-3-3 proteins, PPIA), derived from different brain cell types, strongly correlated with fluid as well as imaging biomarkers and increased early in the AD continuum. Among them, the proteins SMOC1 and CNN3 were highly associated with Aβ pathology, while the 14-3-3 proteins YWHAZ and YWHAE as well as PPIA demonstrated a strong association with both Aβ and tau pathology as indexed by PET. Endo-lysosomal proteins (e.g., HEXB, TPP1, SIAE) increased early in abundance alongside neurodegeneration-related proteins, and were followed by increases in metabolic proteins such as ALDOA, MDH1, and GOT1 at the mild cognitive impairment (MCI) stage. Finally, later AD stages were characterized by decreases in synaptic/membrane proteins (e.g., NPTX2).CONCLUSIONSOur study identified proxies of Aβ and tau pathology, indexed by PET, (SMOC1, YWHAE, CNN3) and highlighted the dynamic fluctuations of the CSF proteome over the disease course, identifying candidate biomarkers for disease staging beyond Aβ and tau.
{"title":"Cerebrospinal fluid proteome profiling across the Alzheimer's disease continuum: a step towards solving the equation for 'X'.","authors":"Sophia Weiner,Mathias Sauer,Laia Montoliu-Gaya,Andrea L Benedet,Nicholas J Ashton,Fernando Gonzalez-Ortiz,Joel Simrén,Nesrine Rahmouni,Cecile Tissot,Joseph Therriault,Stijn Servaes,Jenna Stevenson,Ville Leinonen,Tuomas Rauramaa,Mikko Hiltunen,Pedro Rosa-Neto,Kaj Blennow,Henrik Zetterberg,Johan Gobom","doi":"10.1186/s13024-025-00841-0","DOIUrl":"https://doi.org/10.1186/s13024-025-00841-0","url":null,"abstract":"BACKGROUNDWhile the temporal profile of amyloid (Aβ) and tau cerebrospinal fluid (CSF) biomarkers along the Alzheimer's disease (AD) continuum is well-studied, chronological changes of CSF proteins reflecting other disease-relevant processes, denoted 'X' in the ATX(N) framework, remain poorly understood.METHODSUsing an untargeted mass spectrometric approach termed tandem mass tag (TMT), we quantified over 1500 CSF proteins across the AD continuum in three independent cohorts, finely staged by Aβ/tau positron emission tomography (PET), fluid biomarkers, or brain biopsy. Weighted protein co-expression network analysis identified clusters of proteins robustly correlating in all three cohorts which sequentially changed with AD progression. Obtained protein clusters were correlated with fluid biomarker measurements (phosphorylated tau (p-tau) species including p-tau181, p-tau217, and p-tau205, as well as Aβ), Aβ/tau PET imaging, and clinical parameters to discern disease-relevant clusters which were modelled across the AD continuum.RESULTSNeurodegeneration-related proteins (e.g., 14-3-3 proteins, PPIA), derived from different brain cell types, strongly correlated with fluid as well as imaging biomarkers and increased early in the AD continuum. Among them, the proteins SMOC1 and CNN3 were highly associated with Aβ pathology, while the 14-3-3 proteins YWHAZ and YWHAE as well as PPIA demonstrated a strong association with both Aβ and tau pathology as indexed by PET. Endo-lysosomal proteins (e.g., HEXB, TPP1, SIAE) increased early in abundance alongside neurodegeneration-related proteins, and were followed by increases in metabolic proteins such as ALDOA, MDH1, and GOT1 at the mild cognitive impairment (MCI) stage. Finally, later AD stages were characterized by decreases in synaptic/membrane proteins (e.g., NPTX2).CONCLUSIONSOur study identified proxies of Aβ and tau pathology, indexed by PET, (SMOC1, YWHAE, CNN3) and highlighted the dynamic fluctuations of the CSF proteome over the disease course, identifying candidate biomarkers for disease staging beyond Aβ and tau.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"38 1","pages":"52"},"PeriodicalIF":15.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-03DOI: 10.1186/s13024-025-00840-1
Xiaojie Zhao, Yan Li, Siwei Zhang, Ari Sudwarts, Hanwen Zhang, Alena Kozlova, Matthew J. Moulton, Lindsey D. Goodman, Zhiping P. Pang, Alan R. Sanders, Hugo J. Bellen, Gopal Thinakaran, Jubao Duan
Genome-wide association studies (GWAS) of Alzheimer’s disease (AD) have identified a plethora of risk loci. However, the disease variants/genes and the underlying mechanisms have not been extensively studied. Bulk ATAC-seq was performed in induced pluripotent stem cells (iPSCs) differentiated various brain cell types to identify allele-specific open chromatin (ASoC) SNPs. CRISPR-Cas9 editing generated isogenic pairs, which were then differentiated into glutamatergic neurons (iGlut). Transcriptomic analysis and functional studies of iGlut co-cultured with mouse astrocytes assessed neuronal excitability and lipid droplet formation. We identified a putative causal SNP of CLU that impacted neuronal chromatin accessibility to transcription-factor(s), with the AD protective allele upregulating neuronal CLU and promoting neuron excitability. And, neuronal CLU facilitated neuron-to-glia lipid transfer and astrocytic lipid droplet formation coupled with reactive oxygen species (ROS) accumulation. These changes caused astrocytes to uptake less glutamate thereby altering neuron excitability. For a strong AD-associated locus near Clusterin (CLU), we connected an AD protective allele to a role of neuronal CLU in promoting neuron excitability through lipid-mediated neuron-glia communication. Our study provides insights into how CLU confers resilience to AD through neuron-glia interactions.
{"title":"Alzheimer’s disease protective allele of Clusterin modulates neuronal excitability through lipid-droplet-mediated neuron-glia communication","authors":"Xiaojie Zhao, Yan Li, Siwei Zhang, Ari Sudwarts, Hanwen Zhang, Alena Kozlova, Matthew J. Moulton, Lindsey D. Goodman, Zhiping P. Pang, Alan R. Sanders, Hugo J. Bellen, Gopal Thinakaran, Jubao Duan","doi":"10.1186/s13024-025-00840-1","DOIUrl":"https://doi.org/10.1186/s13024-025-00840-1","url":null,"abstract":"Genome-wide association studies (GWAS) of Alzheimer’s disease (AD) have identified a plethora of risk loci. However, the disease variants/genes and the underlying mechanisms have not been extensively studied. Bulk ATAC-seq was performed in induced pluripotent stem cells (iPSCs) differentiated various brain cell types to identify allele-specific open chromatin (ASoC) SNPs. CRISPR-Cas9 editing generated isogenic pairs, which were then differentiated into glutamatergic neurons (iGlut). Transcriptomic analysis and functional studies of iGlut co-cultured with mouse astrocytes assessed neuronal excitability and lipid droplet formation. We identified a putative causal SNP of CLU that impacted neuronal chromatin accessibility to transcription-factor(s), with the AD protective allele upregulating neuronal CLU and promoting neuron excitability. And, neuronal CLU facilitated neuron-to-glia lipid transfer and astrocytic lipid droplet formation coupled with reactive oxygen species (ROS) accumulation. These changes caused astrocytes to uptake less glutamate thereby altering neuron excitability. For a strong AD-associated locus near Clusterin (CLU), we connected an AD protective allele to a role of neuronal CLU in promoting neuron excitability through lipid-mediated neuron-glia communication. Our study provides insights into how CLU confers resilience to AD through neuron-glia interactions.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"54 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143902933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-29DOI: 10.1186/s13024-025-00830-3
Henna Martiskainen, Roosa-Maria Willman, Päivi Harju, Sami Heikkinen, Mette Heiskanen, Stephan A. Müller, Rosa Sinisalo, Mari Takalo, Petra Mäkinen, Teemu Kuulasmaa, Viivi Pekkala, Ana Galván del Rey, Sini-Pauliina Juopperi, Heli Jeskanen, Inka Kervinen, Kirsi Saastamoinen, Marja Niiranen, Sami V. Heikkinen, Mitja I. Kurki, Jarkko Marttila, Petri I. Mäkinen, Hannah Rostalski, Tomi Hietanen, Tiia Ngandu, Jenni Lehtisalo, Céline Bellenguez, Jean-Charles Lambert, Christian Haass, Juha Rinne, Juhana Hakumäki, Tuomas Rauramaa, Johanna Krüger, Hilkka Soininen, Annakaisa Haapasalo, Stefan F. Lichtenthaler, Ville Leinonen, Eino Solje, Mikko Hiltunen
Biallelic loss-of-function variants in TYROBP and TREM2 cause autosomal recessive presenile dementia with bone cysts known as Nasu-Hakola disease (NHD, alternatively polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL). Some other TREM2 variants contribute to the risk of Alzheimer’s disease (AD) and frontotemporal dementia, while deleterious TYROBP variants are globally extremely rare and their role in neurodegenerative diseases remains unclear. The population history of Finns has favored the enrichment of deleterious founder mutations, including a 5.2 kb deletion encompassing exons 1–4 of TYROBP and causing NHD in homozygous carriers. We used here a proxy marker to identify monoallelic TYROBP deletion carriers in the Finnish biobank study FinnGen combining genome and health registry data of 520,210 Finns. We show that monoallelic TYROBP deletion associates with an increased risk and earlier onset age of AD and dementia when compared to noncarriers. In addition, we present the first reported case of a monoallelic TYROBP deletion carrier with NHD-type bone cysts. Mechanistically, monoallelic TYROBP deletion leads to decreased levels of DAP12 protein (encoded by TYROBP) in myeloid cells. Using transcriptomic and proteomic analyses of human monocyte-derived microglia-like cells, we show that upon lipopolysaccharide stimulation monoallelic TYROBP deletion leads to the upregulation of the inflammatory response and downregulation of the unfolded protein response when compared to cells with two functional copies of TYROBP. Collectively, our findings indicate TYROBP deletion as a novel risk factor for AD and suggest specific pathways for therapeutic targeting.
{"title":"Monoallelic TYROBP deletion is a novel risk factor for Alzheimer’s disease","authors":"Henna Martiskainen, Roosa-Maria Willman, Päivi Harju, Sami Heikkinen, Mette Heiskanen, Stephan A. Müller, Rosa Sinisalo, Mari Takalo, Petra Mäkinen, Teemu Kuulasmaa, Viivi Pekkala, Ana Galván del Rey, Sini-Pauliina Juopperi, Heli Jeskanen, Inka Kervinen, Kirsi Saastamoinen, Marja Niiranen, Sami V. Heikkinen, Mitja I. Kurki, Jarkko Marttila, Petri I. Mäkinen, Hannah Rostalski, Tomi Hietanen, Tiia Ngandu, Jenni Lehtisalo, Céline Bellenguez, Jean-Charles Lambert, Christian Haass, Juha Rinne, Juhana Hakumäki, Tuomas Rauramaa, Johanna Krüger, Hilkka Soininen, Annakaisa Haapasalo, Stefan F. Lichtenthaler, Ville Leinonen, Eino Solje, Mikko Hiltunen","doi":"10.1186/s13024-025-00830-3","DOIUrl":"https://doi.org/10.1186/s13024-025-00830-3","url":null,"abstract":"Biallelic loss-of-function variants in TYROBP and TREM2 cause autosomal recessive presenile dementia with bone cysts known as Nasu-Hakola disease (NHD, alternatively polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL). Some other TREM2 variants contribute to the risk of Alzheimer’s disease (AD) and frontotemporal dementia, while deleterious TYROBP variants are globally extremely rare and their role in neurodegenerative diseases remains unclear. The population history of Finns has favored the enrichment of deleterious founder mutations, including a 5.2 kb deletion encompassing exons 1–4 of TYROBP and causing NHD in homozygous carriers. We used here a proxy marker to identify monoallelic TYROBP deletion carriers in the Finnish biobank study FinnGen combining genome and health registry data of 520,210 Finns. We show that monoallelic TYROBP deletion associates with an increased risk and earlier onset age of AD and dementia when compared to noncarriers. In addition, we present the first reported case of a monoallelic TYROBP deletion carrier with NHD-type bone cysts. Mechanistically, monoallelic TYROBP deletion leads to decreased levels of DAP12 protein (encoded by TYROBP) in myeloid cells. Using transcriptomic and proteomic analyses of human monocyte-derived microglia-like cells, we show that upon lipopolysaccharide stimulation monoallelic TYROBP deletion leads to the upregulation of the inflammatory response and downregulation of the unfolded protein response when compared to cells with two functional copies of TYROBP. Collectively, our findings indicate TYROBP deletion as a novel risk factor for AD and suggest specific pathways for therapeutic targeting.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"8 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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