Pub Date : 2025-08-06DOI: 10.1186/s13024-025-00880-7
Michael T. Maloney, Xiang Wang, Rajarshi Ghosh, Shan V. Andrews, Romeo Maciuca, Shababa T. Masoud, Maayan Agam, Richard M. Caprioli, Giuseppe Astarita, Vitaliy V. Bondar, John Chen, Chi-Lu Chiu, Sonnet S. Davis, Audrey Cheuk-Nga Ho, Hoang N. Nguyen, Nicholas E. Propson, Michelle L. Reyzer, Oliver B. Davis, Matthew C. Deen, Sha Zhu, Gilbert Di Paolo, David J. Vocadlo, Anthony A Estrada, Javier de Vicente, Joseph W. Lewcock, Annie Arguello, Jung H. Suh, Sarah Huntwork-Rodriguez, Anastasia G. Henry
Pathogenic variants in LRRK2 lead to increased kinase activity, and LRRK2 kinase inhibition is being explored in clinical studies as a therapeutic approach for Parkinson’s Disease (PD). LRRK2 inhibitors reduce urine levels of bis(monoacylglycerol)phosphate (BMP), a key endolysosomal lipid involved in glycosphingolipid (GSL) catabolism, in preclinical models and clinical subjects. However, how LRRK2 regulates BMP and its significance with respect to lysosomal dysfunction in PD are poorly defined. Using a combination of genetic and pharmacological approaches to modulate LRRK2 kinase activity, we explored the mechanisms by which LRRK2 can regulate the levels of BMP and PD-relevant GSLs across cellular models, including iPSC-derived microglia, and in tissues and biofluids from mice using mass spectrometry. The impact of LRRK2 activity on various aspects of lysosomal function, including endolysosomal GCase activity, was assessed using live-cell imaging and lysosomal immunoprecipitation. We employed imaging mass-spectrometry and FACS-based methods to specifically examine how LRRK2 modulates BMP and GSL levels across different cell types and regions of the brain. To confirm the relevance of our findings to disease, we measured lysosomal biomarkers in urine and cerebrospinal fluid (CSF) from human subjects carrying variants in LRRK2 associated with PD risk and from subjects dosed with a LRRK2 kinase inhibitor. Our data demonstrate that LRRK2 can employ distinct mechanisms to control intracellular BMP levels and modulate lysosomal homeostasis depending on the tissue examined. We show that LRRK2 deletion or inhibition lowers urine BMP levels by reducing the secretion of BMP-containing vesicles from kidney into urine. In other cell types such as microglia, LRRK2-mediated inhibition of β-glucocerebrosidase (GCase), a PD-linked enzyme involved in GSL catabolism, leads to lysosomal GSL accumulation and increases BMP levels as a compensatory response to restore lysosomal homeostasis. LRRK2 inhibition normalizes lysosomal function and reduces GSL levels in preclinical models and CSF from LRRK2-PD patients. Our study highlights the therapeutic potential of LRRK2 kinase inhibition to improve PD-associated lysosomal dysfunction and supports the utility of GSLs as CSF-based biomarkers of LRRK2 activity. This work includes results from the following phase 1b study in PD patients: ClinicalTrials.gov ID: NCT03710707; https://clinicaltrials.gov/study/NCT03710707?intr=dnl201&rank=2 . The date of registration was 10/18/2018.
{"title":"LRRK2 kinase activity regulates Parkinson’s disease-relevant lipids at the lysosome","authors":"Michael T. Maloney, Xiang Wang, Rajarshi Ghosh, Shan V. Andrews, Romeo Maciuca, Shababa T. Masoud, Maayan Agam, Richard M. Caprioli, Giuseppe Astarita, Vitaliy V. Bondar, John Chen, Chi-Lu Chiu, Sonnet S. Davis, Audrey Cheuk-Nga Ho, Hoang N. Nguyen, Nicholas E. Propson, Michelle L. Reyzer, Oliver B. Davis, Matthew C. Deen, Sha Zhu, Gilbert Di Paolo, David J. Vocadlo, Anthony A Estrada, Javier de Vicente, Joseph W. Lewcock, Annie Arguello, Jung H. Suh, Sarah Huntwork-Rodriguez, Anastasia G. Henry","doi":"10.1186/s13024-025-00880-7","DOIUrl":"https://doi.org/10.1186/s13024-025-00880-7","url":null,"abstract":"Pathogenic variants in LRRK2 lead to increased kinase activity, and LRRK2 kinase inhibition is being explored in clinical studies as a therapeutic approach for Parkinson’s Disease (PD). LRRK2 inhibitors reduce urine levels of bis(monoacylglycerol)phosphate (BMP), a key endolysosomal lipid involved in glycosphingolipid (GSL) catabolism, in preclinical models and clinical subjects. However, how LRRK2 regulates BMP and its significance with respect to lysosomal dysfunction in PD are poorly defined. Using a combination of genetic and pharmacological approaches to modulate LRRK2 kinase activity, we explored the mechanisms by which LRRK2 can regulate the levels of BMP and PD-relevant GSLs across cellular models, including iPSC-derived microglia, and in tissues and biofluids from mice using mass spectrometry. The impact of LRRK2 activity on various aspects of lysosomal function, including endolysosomal GCase activity, was assessed using live-cell imaging and lysosomal immunoprecipitation. We employed imaging mass-spectrometry and FACS-based methods to specifically examine how LRRK2 modulates BMP and GSL levels across different cell types and regions of the brain. To confirm the relevance of our findings to disease, we measured lysosomal biomarkers in urine and cerebrospinal fluid (CSF) from human subjects carrying variants in LRRK2 associated with PD risk and from subjects dosed with a LRRK2 kinase inhibitor. Our data demonstrate that LRRK2 can employ distinct mechanisms to control intracellular BMP levels and modulate lysosomal homeostasis depending on the tissue examined. We show that LRRK2 deletion or inhibition lowers urine BMP levels by reducing the secretion of BMP-containing vesicles from kidney into urine. In other cell types such as microglia, LRRK2-mediated inhibition of β-glucocerebrosidase (GCase), a PD-linked enzyme involved in GSL catabolism, leads to lysosomal GSL accumulation and increases BMP levels as a compensatory response to restore lysosomal homeostasis. LRRK2 inhibition normalizes lysosomal function and reduces GSL levels in preclinical models and CSF from LRRK2-PD patients. Our study highlights the therapeutic potential of LRRK2 kinase inhibition to improve PD-associated lysosomal dysfunction and supports the utility of GSLs as CSF-based biomarkers of LRRK2 activity. This work includes results from the following phase 1b study in PD patients: ClinicalTrials.gov ID: NCT03710707; https://clinicaltrials.gov/study/NCT03710707?intr=dnl201&rank=2 . The date of registration was 10/18/2018.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"12 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792628","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 : 2025-08-06DOI: 10.1186/s13024-025-00872-7
Heike Hering, Thierry Bussiere, Chia-Chen Liu, Kelly E. Glajch, Andreas Weihofen, Jane Grogan, Dominic M. Walsh
After decades of disappointment, three disease-modifying therapies for Alzheimer’s disease (AD) have been approved since 2021. Burgeoning clinical data on these amyloid β-protein (Aβ) targeting drugs validate the amyloid cascade hypothesis as a molecular roadmap for the development of yet more effective therapeutics and offer a template for drugging other AD-associated aggregation-prone proteins. While there remains much to be learned about the molecular pathology of AD, the current state of knowledge is sufficient to expedite the delivery of new drugs. Mindful of the urgent need of patients, we recommend prioritizing efforts in four directions: finishing the job on Aβ, accelerating and diversifying efforts on tau, and expanding discovery on apolipoprotein E and ⍺-synuclein. For each target, we explain the scientific premise, current efforts, and possible new approaches. In the short- and medium-term, we advocate focusing on the technical innovations required to better drug these already well validated targets. While the focus of this review is on expediating development of monotherapies, the subsequent approval of such agents will enable add-on or combination approaches best suited to individual patients.
{"title":"A manifesto for Alzheimer’s disease drug discovery in the era of disease-modifying therapies","authors":"Heike Hering, Thierry Bussiere, Chia-Chen Liu, Kelly E. Glajch, Andreas Weihofen, Jane Grogan, Dominic M. Walsh","doi":"10.1186/s13024-025-00872-7","DOIUrl":"https://doi.org/10.1186/s13024-025-00872-7","url":null,"abstract":"After decades of disappointment, three disease-modifying therapies for Alzheimer’s disease (AD) have been approved since 2021. Burgeoning clinical data on these amyloid β-protein (Aβ) targeting drugs validate the amyloid cascade hypothesis as a molecular roadmap for the development of yet more effective therapeutics and offer a template for drugging other AD-associated aggregation-prone proteins. While there remains much to be learned about the molecular pathology of AD, the current state of knowledge is sufficient to expedite the delivery of new drugs. Mindful of the urgent need of patients, we recommend prioritizing efforts in four directions: finishing the job on Aβ, accelerating and diversifying efforts on tau, and expanding discovery on apolipoprotein E and ⍺-synuclein. For each target, we explain the scientific premise, current efforts, and possible new approaches. In the short- and medium-term, we advocate focusing on the technical innovations required to better drug these already well validated targets. While the focus of this review is on expediating development of monotherapies, the subsequent approval of such agents will enable add-on or combination approaches best suited to individual patients.\u0000","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"13 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786533","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 : 2025-08-05DOI: 10.1186/s13024-025-00881-6
Cassia R Overk, Anna Cartier, Gideon Shaked, Edward Rockenstein, Kiren Ubhi, Brian Spencer, Diana L Price, Christina Patrick, Paula Desplats, Eliezer Masliah
Retraction Note
The Editorial team has retracted this article.
After publication, concerns were raised regarding some of the data presented in the figures. Specifically:
Panels Non tg and APP tg in the second row of Fig. 5A appear to overlap;
Panels Non tg in the third rows of Fig. 6B and D appear to overlap;
Panels APP tg and alpha-syn tg in the first row of Fig. 7D appear to overlap;
Panels Non-tg in the second rows of Fig. 7B and D appear to overlap;
Panels APP tg and alpha-syn tg in the third row of Fig. 7D appear to overlap;
Some blots in Fig. 9c appear to have similar bands between the two LV-control groups (vehicle and Aβ1–42).
The authors have stated that these errors occurred during figure preparation. However, due to the number of concerns, the Editors-in-Chief no longer have confidence in the presented data.
Cassia R Overk and Eliezer Masliah disagree with this retraction. The other authors have not responded to any correspondence from the editor or publisher about this retraction.
Authors and Affiliations
Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA
Cassia R Overk, Anna Cartier, Gideon Shaked, Edward Rockenstein, Kiren Ubhi, Brian Spencer, Christina Patrick, Paula Desplats & Eliezer Masliah
Neuropore Therapies, Inc, San Diego, CA, 92121, USA
Diana L Price
Department of Pathology, University of California, San Diego, La Jolla, CA, USA
Eliezer Masliah
Authors
Cassia R OverkView author publications
Search author on:PubMedGoogle Scholar
Anna CartierView author publications
Search author on:PubMedGoogle Scholar
Gideon ShakedView author publications
Search author on:PubMedGoogle Scholar
Edward RockensteinView author publications
Search author on:PubMedGoogle Scholar
Kiren UbhiView author publications
Search author on:PubMedGoogle Scholar
Brian SpencerView author publications
Search author on:PubMedGoogle Scholar
Diana L PriceView author publications
Search author on:PubMedGoogle Scholar
Christina PatrickView author publications
Search author on:PubMedGoogle Scholar
Paula DesplatsView author publications
Search author on:PubMed <
编辑团队撤回了这篇文章。在发表后，人们对图表中的一些数据提出了担忧。明确:板非tg和应用tg在图5的第二行出现重叠;板非tg在第三排图6 b和D似乎重叠;面板应用tg和alpha-syn tg在图7 D的第一行出现重叠;面板Non-tg第二行图7 b和D似乎重叠;面板应用tg和alpha-syn tg在图7 D的第三行出现重叠;一些污点在图9 c LV-control两组之间似乎也有类似的乐队(车辆和β1-42)。作者指出，这些错误发生在数字准备过程中。但是，由于涉及的问题太多，主编们对所提供的数据不再有信心。Cassia R Overk和Eliezer Masliah不同意这一撤回。其他作者没有回复编辑或出版商关于此次撤稿的任何信件。加州大学圣地亚哥分校神经科学系acassia R Overk， Anna Cartier, Gideon Shaked, Edward Rockenstein, Kiren Ubhi, Brian Spencer, Christina Patrick, Paula Desplats &；Eliezer MasliahNeuropore therapeutics, Inc, San Diego， CA, 92121, USADiana L price，加州大学病理学系，San Diego, La Jolla， CAUSAEliezer MasliahAuthorsCassia R OverkView作者publationssearch author on:PubMed谷歌ScholarAnna CartierView作者publationssearch author on:PubMed谷歌ScholarGideon ShakedView作者publationssearch author on:PubMed谷歌scholarward RockensteinView作者publationssearch author on:PubMed谷歌ScholarKiren UbhiView作者publationssearch author on:PubMed谷歌ScholarBrian SpencerView作者publationssearch author on:PubMed谷歌ScholarDiana L PriceView作者publationssearch author on:PubMed b谷歌ScholarChristina PatrickView作者publationssearch author on:PubMed谷歌ScholarPaula DesplatsView作者publationssearch author on:PubMed谷歌ScholarEliezer MasliahView作者publationssearch author on:PubMed谷歌scholar通讯作者与Eliezer Masliah通信。出版方声明：对于已出版地图的管辖权要求和机构关系，普林格·自然保持中立。开放获取本文遵循知识共享署名4.0国际许可协议，该协议允许以任何媒介或格式使用、共享、改编、分发和复制，只要您适当地注明原作者和来源，提供知识共享许可协议的链接，并注明是否进行了更改。本文中的图像或其他第三方材料包含在文章的知识共享许可协议中，除非在材料的署名中另有说明。如果材料未包含在文章的知识共享许可中，并且您的预期用途不被法律法规允许或超过允许的用途，您将需要直接获得版权所有者的许可。要查看本许可的副本，请访问http://creativecommons.org/licenses/by/4.0/。知识共享公共领域免责条款（http://creativecommons.org/publicdomain/zero/1.0/）适用于本文中提供的数据，除非在数据的署名中另有说明。引用本文overk， c.r., Cartier， A, Shaked， G.等人。注：积累α-突触核蛋白片段的海马神经元细胞更容易通过mGluR5 -对Aβ寡聚物的毒性作用影响路易体痴呆。神经退行性病变，20,87（2025）。https://doi.org/10.1186/s13024-025-00881-6Download citationpublish: 05 August 2025DOI: https://doi.org/10.1186/s13024-025-00881-6Share这篇文章任何你分享了以下链接的人都可以阅读到这篇文章：获取可共享链接对不起，这篇文章目前没有可共享的链接。复制到剪贴板由施普林格自然共享内容倡议提供
{"title":"Retraction Note: Hippocampal neuronal cells that accumulate α-synuclein fragments are more vulnerable to Aβ oligomer toxicity via mGluR5– implications for dementia with lewy bodies","authors":"Cassia R Overk, Anna Cartier, Gideon Shaked, Edward Rockenstein, Kiren Ubhi, Brian Spencer, Diana L Price, Christina Patrick, Paula Desplats, Eliezer Masliah","doi":"10.1186/s13024-025-00881-6","DOIUrl":"https://doi.org/10.1186/s13024-025-00881-6","url":null,"abstract":"<p><b>Retraction Note</b></p><p>The Editorial team has retracted this article.</p><p>After publication, concerns were raised regarding some of the data presented in the figures. Specifically:</p><ul>\u0000<li>\u0000<p>Panels <i>Non tg</i> and <i>APP tg</i> in the second row of Fig. 5A appear to overlap;</p>\u0000</li>\u0000<li>\u0000<p>Panels <i>Non tg</i> in the third rows of Fig. 6B and D appear to overlap;</p>\u0000</li>\u0000<li>\u0000<p>Panels <i>APP tg</i> and <i>alpha-syn tg</i> in the first row of Fig. 7D appear to overlap;</p>\u0000</li>\u0000<li>\u0000<p>Panels <i>Non-tg</i> in the second rows of Fig. 7B and D appear to overlap;</p>\u0000</li>\u0000<li>\u0000<p>Panels <i>APP tg</i> and <i>alpha-syn tg</i> in the third row of Fig. 7D appear to overlap;</p>\u0000</li>\u0000<li>\u0000<p>Some blots in Fig. 9c appear to have similar bands between the two LV-control groups (vehicle and Aβ1–42).</p>\u0000</li>\u0000</ul><p>The authors have stated that these errors occurred during figure preparation. However, due to the number of concerns, the Editors-in-Chief no longer have confidence in the presented data.</p><p>Cassia R Overk and Eliezer Masliah disagree with this retraction. The other authors have not responded to any correspondence from the editor or publisher about this retraction.</p><h3>Authors and Affiliations</h3><ol><li><p>Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA</p><p>Cassia R Overk, Anna Cartier, Gideon Shaked, Edward Rockenstein, Kiren Ubhi, Brian Spencer, Christina Patrick, Paula Desplats & Eliezer Masliah</p></li><li><p>Neuropore Therapies, Inc, San Diego, CA, 92121, USA</p><p>Diana L Price</p></li><li><p>Department of Pathology, University of California, San Diego, La Jolla, CA, USA</p><p>Eliezer Masliah</p></li></ol><span>Authors</span><ol><li><span>Cassia R Overk</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Anna Cartier</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Gideon Shaked</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Edward Rockenstein</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Kiren Ubhi</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Brian Spencer</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Diana L Price</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Christina Patrick</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Paula Desplats</span>View author publications<p><span>Search author on:</span><span>PubMed<span> <","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"112 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144778200","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 : 2025-07-26DOI: 10.1186/s13024-025-00876-3
Thibaut Burg, Ludo Van Den Bosch
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting the adult motor system, with no effective treatments available. Despite extensive research efforts, the exact pathological cascade leading to progressive motor neuron degeneration remains elusive. Recent evidence highlights significant modifications in lipid metabolism during ALS progression, even before the onset of motor symptoms. Glycerophospholipids, the primary components of cellular membranes, are frequently altered in ALS patients and models. These lipids not only play a structural role in membranes, but also contribute to cellular metabolism, signaling pathways, and cell type-specific processes such as neuronal transmission and muscle contraction. In this review, we discuss glycerophospholipid physiological functions in the motor system and review recent studies demonstrating their alterations and the possible underlying pathological mechanisms in ALS. Furthermore, we discuss challenges emerging from studying lipid alterations in neurodegeneration and evaluate the therapeutic potential of glycerophospholipids.
{"title":"Glycerophospholipids in ALS: insights into disease mechanisms and clinical implication","authors":"Thibaut Burg, Ludo Van Den Bosch","doi":"10.1186/s13024-025-00876-3","DOIUrl":"https://doi.org/10.1186/s13024-025-00876-3","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting the adult motor system, with no effective treatments available. Despite extensive research efforts, the exact pathological cascade leading to progressive motor neuron degeneration remains elusive. Recent evidence highlights significant modifications in lipid metabolism during ALS progression, even before the onset of motor symptoms. Glycerophospholipids, the primary components of cellular membranes, are frequently altered in ALS patients and models. These lipids not only play a structural role in membranes, but also contribute to cellular metabolism, signaling pathways, and cell type-specific processes such as neuronal transmission and muscle contraction. In this review, we discuss glycerophospholipid physiological functions in the motor system and review recent studies demonstrating their alterations and the possible underlying pathological mechanisms in ALS. Furthermore, we discuss challenges emerging from studying lipid alterations in neurodegeneration and evaluate the therapeutic potential of glycerophospholipids.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"14 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710637","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 : 2025-07-26DOI: 10.1186/s13024-025-00873-6
Hideyuki Takahashi, Stephen M. Strittmatter
Although different neurodegenerative diseases are defined by distinct pathological proteins, they share many common features including protein aggregation. Despite this commonality, most current therapeutic approaches in the field, such as anti-aggregate antibodies, are focused on individual diseases or single neuropathologies with only limited success. The endolysosomal proteins progranulin and TMEM106B were both initially associated with frontotemporal lobar degeneration but have subsequently also been linked to other neurodegenerative diseases. Thus, these proteins are predicted to participate in common pathogenic pathways shared across various neurodegenerative diseases. Importantly, recent discoveries of TMEM106B amyloid fibrils in varied neurodegenerative diseases and glycosphingolipid regulation by progranulin and TMEM106B further support their central roles in cross-disease neurodegenerative mechanisms. This review summarizes recent advances in progranulin and TMEM106B function within the endolysosomal system and neurodegenerative diseases. It describes preclinical models and therapeutic approaches for progranulin- and TMEM106B-associated diseases. We also discuss future direction leading to novel alternative therapies targeting shared mechanisms in neurodegenerative diseases.
{"title":"The role of endolysosomal progranulin and TMEM106B in neurodegenerative diseases","authors":"Hideyuki Takahashi, Stephen M. Strittmatter","doi":"10.1186/s13024-025-00873-6","DOIUrl":"https://doi.org/10.1186/s13024-025-00873-6","url":null,"abstract":"Although different neurodegenerative diseases are defined by distinct pathological proteins, they share many common features including protein aggregation. Despite this commonality, most current therapeutic approaches in the field, such as anti-aggregate antibodies, are focused on individual diseases or single neuropathologies with only limited success. The endolysosomal proteins progranulin and TMEM106B were both initially associated with frontotemporal lobar degeneration but have subsequently also been linked to other neurodegenerative diseases. Thus, these proteins are predicted to participate in common pathogenic pathways shared across various neurodegenerative diseases. Importantly, recent discoveries of TMEM106B amyloid fibrils in varied neurodegenerative diseases and glycosphingolipid regulation by progranulin and TMEM106B further support their central roles in cross-disease neurodegenerative mechanisms. This review summarizes recent advances in progranulin and TMEM106B function within the endolysosomal system and neurodegenerative diseases. It describes preclinical models and therapeutic approaches for progranulin- and TMEM106B-associated diseases. We also discuss future direction leading to novel alternative therapies targeting shared mechanisms in neurodegenerative diseases.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"21 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710705","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}
Alzheimer’s disease (AD) is a multifaceted neurodegenerative disorder with a complex etiology that extends beyond the well-documented amyloid-β and tau pathologies. Growing evidence implicates cerebrovascular dysfunction, particularly brain microvascular endothelial cells (BMECs) dysfunction, as an early contributor to AD pathogenesis. However, how BMECs influence on neighboring astrocytes needs to be further explored. We employed a multi-omics approach integrating bulk RNA sequencing of human BMECs with proteomic analysis of cerebrospinal fluid (CSF) from AD patients and cerebrovascular endothelial extracellular vesicles (CEEVs). The role of identified candidate proteins was investigated in vitro and in vivo utilizing CEEVs transplantation and BMEC-astrocyte co-cultures. Endothelial cell-specific knockdown or treatment with a monoclonal antibody was used to assess the functional consequences on cognitive impairment and AD pathology via two-photon imaging and behavioral experiments on APP/PS1 mice. The elevated endothelium-specific protein Endoglin (ENG) was identified in the brain and serum of AD individuals and APP/PS1 mice, and the supernatant of injured BMECs. ENG was released and delivered to adjacent astrocytes via CEEVs, and subsequently upregulated TGFBRI/Smad3 pathway in astrocytes, leading to astrocyte reactivity and the release of pro-inflammatory cytokines. Endothelial cell-specific ENG knockdown or treating with ENG monoclonal antibody Carotuximab significantly suppressed reactive astrocytes, reduced neuroinflammation, and improved cognitive performance of APP/PS1 mice. This study reveals a novel mechanism by which BMECs-derived ENG, delivered via CEEVs, drives astrocyte reactivity. These findings redefine the role of cerebrovascular dysfunction in AD pathogenesis and identify ENG as both a potential biomarker and a promising therapeutic target for AD.
{"title":"Endothelium-specific endoglin triggers astrocyte reactivity via extracellular vesicles in a mouse model of Alzheimer’s disease","authors":"Pingao Zhang, Chenghuan Song, Jiyun Shi, Zijie Wei, Jing Wang, Wanying Huang, Rui Zhang, Jintao Wang, Xiaoli Yang, Gang Wang, Xiaoling Gao, Yongfang Zhang, Hongzhuan Chen, Hao Wang","doi":"10.1186/s13024-025-00875-4","DOIUrl":"https://doi.org/10.1186/s13024-025-00875-4","url":null,"abstract":"Alzheimer’s disease (AD) is a multifaceted neurodegenerative disorder with a complex etiology that extends beyond the well-documented amyloid-β and tau pathologies. Growing evidence implicates cerebrovascular dysfunction, particularly brain microvascular endothelial cells (BMECs) dysfunction, as an early contributor to AD pathogenesis. However, how BMECs influence on neighboring astrocytes needs to be further explored. We employed a multi-omics approach integrating bulk RNA sequencing of human BMECs with proteomic analysis of cerebrospinal fluid (CSF) from AD patients and cerebrovascular endothelial extracellular vesicles (CEEVs). The role of identified candidate proteins was investigated in vitro and in vivo utilizing CEEVs transplantation and BMEC-astrocyte co-cultures. Endothelial cell-specific knockdown or treatment with a monoclonal antibody was used to assess the functional consequences on cognitive impairment and AD pathology via two-photon imaging and behavioral experiments on APP/PS1 mice. The elevated endothelium-specific protein Endoglin (ENG) was identified in the brain and serum of AD individuals and APP/PS1 mice, and the supernatant of injured BMECs. ENG was released and delivered to adjacent astrocytes via CEEVs, and subsequently upregulated TGFBRI/Smad3 pathway in astrocytes, leading to astrocyte reactivity and the release of pro-inflammatory cytokines. Endothelial cell-specific ENG knockdown or treating with ENG monoclonal antibody Carotuximab significantly suppressed reactive astrocytes, reduced neuroinflammation, and improved cognitive performance of APP/PS1 mice. This study reveals a novel mechanism by which BMECs-derived ENG, delivered via CEEVs, drives astrocyte reactivity. These findings redefine the role of cerebrovascular dysfunction in AD pathogenesis and identify ENG as both a potential biomarker and a promising therapeutic target for AD.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"112 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684670","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 : 2025-07-14DOI: 10.1186/s13024-025-00874-5
Jay M. Yarbro, Him K. Shrestha, Zhen Wang, Xue Zhang, Masihuz Zaman, Mengqi Chu, Xusheng Wang, Gang Yu, Junmin Peng
The advancements of proteomics technologies are shaping Alzheimer's disease (AD) research, revealing new molecular insights and improving biomarker discovery. Here, we summarize major AD proteomics studies since our 2021 review, focusing on disease mechanisms and biomarker identification. Enhanced sensitivity and throughput in proteome profiling have been driven by mass spectrometry (MS)-based approaches and affinity-based platforms (e.g., Olink and SomaScan). Emerging techniques, including single-cell, spatial, and single-molecule proteomics, provide unprecedented resolution in studying cellular heterogeneity and pathological microenvironments (e.g., amyloidome). Multi-cohort analyses of AD brain tissues have revealed consensus protein alterations (n = 866), identifying novel disease-associated proteins validated in functional studies (e.g., MDK/PTN, NTN1, SMOC1, GPNMB, NPTX2, NRN1, VGF, and U1 snRNP). Proteomic studies of AD biofluids have identified distinct disease subtypes, offering candidate proteins for early detection. Comparisons between human tissues and AD mouse models highlight shared pathways in amyloid pathology while underscoring limitations in recapitulating human disease. Combining proteomics with genomics enables protein quantitative trait locus (pQTL) analysis in AD, linking genetic risk factors to protein expression changes. Discrepancies between proteome and transcriptome suggest altered protein turnover in AD. Overall, AD proteomics continues to provide mechanistic insights into disease progression and potential biomarkers for precision medicine.
{"title":"Proteomic landscape of Alzheimer’s disease: emerging technologies, advances and insights (2021 – 2025)","authors":"Jay M. Yarbro, Him K. Shrestha, Zhen Wang, Xue Zhang, Masihuz Zaman, Mengqi Chu, Xusheng Wang, Gang Yu, Junmin Peng","doi":"10.1186/s13024-025-00874-5","DOIUrl":"https://doi.org/10.1186/s13024-025-00874-5","url":null,"abstract":"The advancements of proteomics technologies are shaping Alzheimer's disease (AD) research, revealing new molecular insights and improving biomarker discovery. Here, we summarize major AD proteomics studies since our 2021 review, focusing on disease mechanisms and biomarker identification. Enhanced sensitivity and throughput in proteome profiling have been driven by mass spectrometry (MS)-based approaches and affinity-based platforms (e.g., Olink and SomaScan). Emerging techniques, including single-cell, spatial, and single-molecule proteomics, provide unprecedented resolution in studying cellular heterogeneity and pathological microenvironments (e.g., amyloidome). Multi-cohort analyses of AD brain tissues have revealed consensus protein alterations (n = 866), identifying novel disease-associated proteins validated in functional studies (e.g., MDK/PTN, NTN1, SMOC1, GPNMB, NPTX2, NRN1, VGF, and U1 snRNP). Proteomic studies of AD biofluids have identified distinct disease subtypes, offering candidate proteins for early detection. Comparisons between human tissues and AD mouse models highlight shared pathways in amyloid pathology while underscoring limitations in recapitulating human disease. Combining proteomics with genomics enables protein quantitative trait locus (pQTL) analysis in AD, linking genetic risk factors to protein expression changes. Discrepancies between proteome and transcriptome suggest altered protein turnover in AD. Overall, AD proteomics continues to provide mechanistic insights into disease progression and potential biomarkers for precision medicine.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"13 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144622228","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}
Recent advances in our understanding of non-cell-autonomous mechanisms in neurodegenerative diseases (NDDs) have highlighted microglial dysfunction as a core driver of disease progression. Conditions such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and frontotemporal dementia (FTD) share features of impaired microglial phagocytosis, chronic neuroinflammation, and metabolic dysregulation. These insights have prompted new therapeutic strategies targeting microglial function and emphasized the need for reliable biomarkers to monitor disease progression and treatment response. Well-established therapeutic targets, such as triggering receptor expressed on myeloid cells 2 (TREM2), progranulin (PGRN), and sortilin (SORT1), along with emerging candidates including LILRB4, P2Y6R, TAM receptors, and neuroinflammation-related markers, are discussed alongside novel blood, cerebrospinal fluid (CSF), and imaging biomarkers. Despite notable progress, many of these biomarkers remain restricted to preclinical studies and face translational challenges due to species-specific differences, lack of standardization, and clinical heterogeneity. Emerging technologies—including single-cell omics, spatial transcriptomics, and artificial intelligence (AI)-driven integration of multimodal data—offer new opportunities to align biomarker profiles with evolving disease states and improve patient stratification. Building on the model of companion diagnostics (CDx) in oncology, integrating multimodal biomarker strategies holds promise for guiding personalized interventions, improving clinical outcomes, and deepening our mechanistic understanding of microglial contributions across the neurodegenerative spectrum.
{"title":"Biomarkers and therapeutic strategies targeting microglia in neurodegenerative diseases: current status and future directions","authors":"Min-Young Noh, Hyuk Sung Kwon, Min-Soo Kwon, Minyeop Nahm, Hee Kyung Jin, Jae-sung Bae, Seung Hyun Kim","doi":"10.1186/s13024-025-00867-4","DOIUrl":"https://doi.org/10.1186/s13024-025-00867-4","url":null,"abstract":"Recent advances in our understanding of non-cell-autonomous mechanisms in neurodegenerative diseases (NDDs) have highlighted microglial dysfunction as a core driver of disease progression. Conditions such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and frontotemporal dementia (FTD) share features of impaired microglial phagocytosis, chronic neuroinflammation, and metabolic dysregulation. These insights have prompted new therapeutic strategies targeting microglial function and emphasized the need for reliable biomarkers to monitor disease progression and treatment response. Well-established therapeutic targets, such as triggering receptor expressed on myeloid cells 2 (TREM2), progranulin (PGRN), and sortilin (SORT1), along with emerging candidates including LILRB4, P2Y6R, TAM receptors, and neuroinflammation-related markers, are discussed alongside novel blood, cerebrospinal fluid (CSF), and imaging biomarkers. Despite notable progress, many of these biomarkers remain restricted to preclinical studies and face translational challenges due to species-specific differences, lack of standardization, and clinical heterogeneity. Emerging technologies—including single-cell omics, spatial transcriptomics, and artificial intelligence (AI)-driven integration of multimodal data—offer new opportunities to align biomarker profiles with evolving disease states and improve patient stratification. Building on the model of companion diagnostics (CDx) in oncology, integrating multimodal biomarker strategies holds promise for guiding personalized interventions, improving clinical outcomes, and deepening our mechanistic understanding of microglial contributions across the neurodegenerative spectrum.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"26 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594115","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 : 2025-07-09DOI: 10.1186/s13024-025-00870-9
Yeseong Choi,Won-Suk Chung
Glia, as resident immune and supportive cells of the central nervous system, play a critical role in maintaining brain homeostasis. One of their key homeostatic functions is phagocytic capacity in pruning synapses and removing cellular debris/protein aggregates, a process vital for synaptic plasticity and brain maintenance. However, these phagocytic functions are often dysregulated with aging and in neurodegenerative diseases (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. This review aims to examine the phagocytic roles of glia under both physiological and pathological conditions, with a special focus on their interactions with misfolded protein aggregates, including amyloid beta, tau, alpha synuclein, prion, huntingtin, and TAR DNA-binding protein 43. We also explore the fate of ingested molecules after being phagocytosed by glia-whether they are degraded, accumulate intracellularly, or are transferred between cells-and their implications for disease progression. Finally, we review current therapeutic strategies and the potential approaches for modulating glial phagocytosis to mitigate several NDs. We believe that understanding the exact mechanisms of glial phagocytosis and clearance will serve as key elements in developing future treatments for NDs.
{"title":"Glial phagocytosis for synapse and toxic proteins in neurodegenerative diseases.","authors":"Yeseong Choi,Won-Suk Chung","doi":"10.1186/s13024-025-00870-9","DOIUrl":"https://doi.org/10.1186/s13024-025-00870-9","url":null,"abstract":"Glia, as resident immune and supportive cells of the central nervous system, play a critical role in maintaining brain homeostasis. One of their key homeostatic functions is phagocytic capacity in pruning synapses and removing cellular debris/protein aggregates, a process vital for synaptic plasticity and brain maintenance. However, these phagocytic functions are often dysregulated with aging and in neurodegenerative diseases (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. This review aims to examine the phagocytic roles of glia under both physiological and pathological conditions, with a special focus on their interactions with misfolded protein aggregates, including amyloid beta, tau, alpha synuclein, prion, huntingtin, and TAR DNA-binding protein 43. We also explore the fate of ingested molecules after being phagocytosed by glia-whether they are degraded, accumulate intracellularly, or are transferred between cells-and their implications for disease progression. Finally, we review current therapeutic strategies and the potential approaches for modulating glial phagocytosis to mitigate several NDs. We believe that understanding the exact mechanisms of glial phagocytosis and clearance will serve as key elements in developing future treatments for NDs.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"26 1","pages":"81"},"PeriodicalIF":15.1,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144586441","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 : 2025-07-06DOI: 10.1186/s13024-025-00869-2
Cristina T. Vicente, Tejasvi Niranjan, Elise Coopman, Júlia Faura, Sara Alidadiani, Claudia Schrauwen, Billie J. Matchett, Bavo Heeman, Marleen Van den Broeck, Wouter De Coster, Thuy Nguyen, Julie S. Lau, Saurabh Baheti, Tim de Pooter, Peter De Rijk, Mojca Strazisar, Matt Baker, Mariely DeJesus-Hernandez, NiCole A. Finch, Cyril Pottier, Marka van Blitterswijk, Yan Asmann, Melissa E. Murray, Leonard Petrucelli, Andrew King, Claire Troakes, Safa Al-Sarraj, Robert A. Rissman, Annie Hiniker, Margaret Flanagan, Bret M. Evers, Charles L. White, Carlos Cruchaga, Rudolph Castellani, Jeroen G.J. van Rooij, Merel O. Mol, Harro Seelaar, John C. van Swieten, Björn Oskarsson, Robert Ross Reichard, Aivi T. Nguyen, Keith A. Josephs, Ronald C. Petersen, Nilüfer Ertekin-Taner, Bradley F. Boeve, Neill R. Graff-Radford, Sarah Weckhuysen, Dennis W. Dickson, Rosa Rademakers
In the last decade, the importance of DNA methylation in the functioning of the central nervous system has been highlighted through associations between methylation changes and differential expression of key genes involved in aging and neurodegenerative diseases. In frontotemporal lobar degeneration (FTLD), aberrant methylation has been reported in causal disease genes including GRN and C9orf72; however, the genome-wide contribution of epigenetic changes to the development of FTLD remains largely unexplored. We performed reduced representation bisulfite sequencing of matched pairs of post-mortem tissue from frontal cortex (FCX) and cerebellum (CER) from pathologically confirmed FTLD patients with TDP-43 pathology (FTLD-TDP) further divided into five subtypes and including both sporadic and genetic forms (N = 25 pairs per group), and neuropathologically normal controls (N = 42 pairs). Case-control differential methylation analyses were performed, both at the individual CpG level, and in regions of grouped CpGs (differentially methylated regions; DMRs), either including all genomic locations or only gene promoters. Gene Ontology (GO) analyses were then performed using all differentially methylated genes in each group of sporadic patients. Finally, additional datasets were queried to prioritize candidate genes for follow-up. Using the largest FTLD-TDP DNA methylation dataset generated to date, we identified thousands of differentially methylated CpGs (FCX = 6,520; CER = 7,134) and several hundred DMRs in FTLD-TDP brains (FCX = 134; CER = 219). Of these, less than 10% are shared between pathological subgroups. Combining additional datasets, we identified, validated and replicated hypomethylation of CAMTA1 in TDP-A potentially also impacting additional genes in the locus. GO analysis further implicated DNA methylation in myelination and developmental processes, as well as important disease-relevant mechanisms with subtype specificity such as protein phosphorylation and DNA damage repair in TDP-A, cholesterol biosynthesis in TDP-B, and protein localization in TDP-C. We identify methylation changes in all FTLD-TDP patient groups and show that most changes are unique to a specific pathological FTLD-TDP subtype, suggesting that these subtypes not only have distinct transcriptomic and genetic signatures, but are also epigenetically distinct. Our study constitutes an invaluable resource to the community and highlights the need for further studies to profile additional epigenetic layers within each FTLD-TDP pathological subtype.
{"title":"Methylome analysis of FTLD patients with TDP-43 pathology identifies epigenetic signatures specific to pathological subtypes","authors":"Cristina T. Vicente, Tejasvi Niranjan, Elise Coopman, Júlia Faura, Sara Alidadiani, Claudia Schrauwen, Billie J. Matchett, Bavo Heeman, Marleen Van den Broeck, Wouter De Coster, Thuy Nguyen, Julie S. Lau, Saurabh Baheti, Tim de Pooter, Peter De Rijk, Mojca Strazisar, Matt Baker, Mariely DeJesus-Hernandez, NiCole A. Finch, Cyril Pottier, Marka van Blitterswijk, Yan Asmann, Melissa E. Murray, Leonard Petrucelli, Andrew King, Claire Troakes, Safa Al-Sarraj, Robert A. Rissman, Annie Hiniker, Margaret Flanagan, Bret M. Evers, Charles L. White, Carlos Cruchaga, Rudolph Castellani, Jeroen G.J. van Rooij, Merel O. Mol, Harro Seelaar, John C. van Swieten, Björn Oskarsson, Robert Ross Reichard, Aivi T. Nguyen, Keith A. Josephs, Ronald C. Petersen, Nilüfer Ertekin-Taner, Bradley F. Boeve, Neill R. Graff-Radford, Sarah Weckhuysen, Dennis W. Dickson, Rosa Rademakers","doi":"10.1186/s13024-025-00869-2","DOIUrl":"https://doi.org/10.1186/s13024-025-00869-2","url":null,"abstract":"In the last decade, the importance of DNA methylation in the functioning of the central nervous system has been highlighted through associations between methylation changes and differential expression of key genes involved in aging and neurodegenerative diseases. In frontotemporal lobar degeneration (FTLD), aberrant methylation has been reported in causal disease genes including GRN and C9orf72; however, the genome-wide contribution of epigenetic changes to the development of FTLD remains largely unexplored. We performed reduced representation bisulfite sequencing of matched pairs of post-mortem tissue from frontal cortex (FCX) and cerebellum (CER) from pathologically confirmed FTLD patients with TDP-43 pathology (FTLD-TDP) further divided into five subtypes and including both sporadic and genetic forms (N = 25 pairs per group), and neuropathologically normal controls (N = 42 pairs). Case-control differential methylation analyses were performed, both at the individual CpG level, and in regions of grouped CpGs (differentially methylated regions; DMRs), either including all genomic locations or only gene promoters. Gene Ontology (GO) analyses were then performed using all differentially methylated genes in each group of sporadic patients. Finally, additional datasets were queried to prioritize candidate genes for follow-up. Using the largest FTLD-TDP DNA methylation dataset generated to date, we identified thousands of differentially methylated CpGs (FCX = 6,520; CER = 7,134) and several hundred DMRs in FTLD-TDP brains (FCX = 134; CER = 219). Of these, less than 10% are shared between pathological subgroups. Combining additional datasets, we identified, validated and replicated hypomethylation of CAMTA1 in TDP-A potentially also impacting additional genes in the locus. GO analysis further implicated DNA methylation in myelination and developmental processes, as well as important disease-relevant mechanisms with subtype specificity such as protein phosphorylation and DNA damage repair in TDP-A, cholesterol biosynthesis in TDP-B, and protein localization in TDP-C. We identify methylation changes in all FTLD-TDP patient groups and show that most changes are unique to a specific pathological FTLD-TDP subtype, suggesting that these subtypes not only have distinct transcriptomic and genetic signatures, but are also epigenetically distinct. Our study constitutes an invaluable resource to the community and highlights the need for further studies to profile additional epigenetic layers within each FTLD-TDP pathological subtype.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"46 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144565679","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：