Molecular Neurodegeneration最新文献

{"title":"The UFMylation pathway is impaired in Alzheimer’s disease","authors":"Tingxiang Yan, Michael G. Heckman, Emily C. Craver, Chia-Chen Liu, Bailey D. Rawlinson, Xue Wang, Melissa E. Murray, Dennis W. Dickson, Nilufer Ertekin-Taner, Zhenkun Lou, Guojun Bu, Wolfdieter Springer, Fabienne C. Fiesel","doi":"10.1186/s13024-024-00784-y","DOIUrl":"https://doi.org/10.1186/s13024-024-00784-y","url":null,"abstract":"Alzheimer’s disease (AD) is characterized by the presence of neurofibrillary tangles made of hyperphosphorylated tau and senile plaques composed of beta-amyloid. These pathognomonic deposits have been implicated in the pathogenesis, although the molecular mechanisms and consequences remain undetermined. UFM1 is an important, but understudied ubiquitin-like protein that is covalently attached to substrates. UFMylation has recently been identified as major modifier of tau aggregation upon seeding in experimental models. However, potential alterations of the UFM1 pathway in human AD brain have not been investigated yet. Here we used frontal and temporal cortex samples from individuals with or without AD to measure the protein levels of the UFMylation pathway in human brain. We used multivariable regression analyses followed by Bonferroni correction for multiple testing to analyze associations of the UFMylation pathway with neuropathological characteristics, primary biochemical measurements of tau and additional biochemical markers from the same cases. We further studied associations of the UFMylation cascade with cellular stress pathways using Spearman correlations with bulk RNAseq expression data and functionally validated these interactions using gene-edited neurons that were generated by CRISPR-Cas9. Compared to controls, human AD brain had increased protein levels of UFM1. Our data further indicates that this increase mainly reflects conjugated UFM1 indicating hyperUFMylation in AD. UFMylation was strongly correlated with pathological tau in both AD-affected brain regions. In addition, we found that the levels of conjugated UFM1 were negatively correlated with soluble levels of the deUFMylation enzyme UFSP2. Functional analysis of UFM1 and/or UFSP2 knockout neurons revealed that the DNA damage response as well as the unfolded protein response are perturbed by changes in neuronal UFM1 signaling. There are marked changes in the UFMylation pathway in human AD brain. These changes are significantly associated with pathological tau, supporting the idea that the UFMylation cascade might indeed act as a modifier of tau pathology in human brain. Our study further nominates UFSP2 as an attractive target to reduce the hyperUFMylation observed in AD brain but also underscores the critical need to identify risks and benefits of manipulating the UFMylation pathway as potential therapeutic avenue for AD.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"12 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849129","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}

{"title":"Mystery of gamma wave stimulation in brain disorders","authors":"Qianting Deng, Chongyun Wu, Emily Parker, Jing Zhu, Timon Cheng-Yi Liu, Rui Duan, Luodan Yang","doi":"10.1186/s13024-024-00785-x","DOIUrl":"https://doi.org/10.1186/s13024-024-00785-x","url":null,"abstract":"Neuronal oscillations refer to rhythmic and periodic fluctuations of electrical activity in the central nervous system that arise from the cellular properties of diverse neuronal populations and their interactions. Specifically, gamma oscillations play a crucial role in governing the connectivity between distinct brain regions, which are essential in perception, motor control, memory, and emotions. In this context, we recapitulate various current stimulation methods to induce gamma entrainment. These methods include sensory stimulation, optogenetic modulation, photobiomodulation, and transcranial electrical or magnetic stimulation. Simultaneously, we explore the association between abnormal gamma oscillations and central nervous system disorders such as Alzheimer’s disease, Parkinson’s disease, stroke, schizophrenia, and autism spectrum disorders. Evidence suggests that gamma entrainment-inducing stimulation methods offer notable neuroprotection, although somewhat controversial. This review comprehensively discusses the functional role of gamma oscillations in higher-order brain activities from both physiological and pathological perspectives, emphasizing gamma entrainment as a potential therapeutic approach for neuropsychiatric disorders. Additionally, we discuss future opportunities and challenges in implementing such strategies.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"64 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849124","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}

{"title":"Correction: The Parkinson’s disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons","authors":"Jace Jones-Tabah, Kathy He, Nathan Karpilovsky, Konstantin Senkevich, Ghislaine Deyab, Isabella Pietrantonio, Thomas Goiran, Yuting Cousineau, Daria Nikanorova, Taylor Goldsmith, Esther del Cid Pellitero, Carol X.-Q. Chen, Wen Luo, Zhipeng You, Narges Abdian, Jamil Ahmad, Jennifer A. Ruskey, Farnaz Asayesh, Dan Spiegelman, Stanley Fahn, Cheryl Waters, Oury Monchi, Yves Dauvilliers, Nicolas Dupré, Irina Miliukhina, Alla Timofeeva, Anton Emelyanov, Sofya Pchelina, Lior Greenbaum, Sharon Hassin-Baer, Roy N. Alcalay, Austen Milnerwood, Thomas M. Durcan, Ziv Gan-Or, Edward A. Fon","doi":"10.1186/s13024-024-00791-z","DOIUrl":"https://doi.org/10.1186/s13024-024-00791-z","url":null,"abstract":"<p><b>Correction</b><b>: </b><b>Mol Neurodegeneration 19, 88 (2024)</b></p><p><b>https://doi.org/10.1186/s13024-024-00779-9</b></p><br/><p>The authors wish to note the Grant ID, MFFF – 007905 relating to the mentioned grants to ZGO and EAF from the Michael J. Fox Foundation which was mistakenly omitted from the original article [1].</p><p>The authors also wish to note that Lior Greenbaum is only affiliated to affiliation #14 (Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel).</p><ol data-track-component=\"outbound reference\" data-track-context=\"references section\"><li data-counter=\"1.\"><p>Jones-Tabah J, He K, Karpilovsky N, et al. The Parkinson’s disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons. Mol Neurodegeneration. 2024;19:88. https://doi.org/10.1186/s13024-024-00779-9.</p><p>Article CAS Google Scholar </p></li></ol><p>Download references<svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-download-medium\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></p><h3>Authors and Affiliations</h3><ol><li><p>Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, McGill Parkinson Program, Montreal Neurological Institute-Hospital, McGill University, Montreal, Québec, Canada</p><p>Jace Jones-Tabah, Kathy He, Nathan Karpilovsky, Konstantin Senkevich, Ghislaine Deyab, Isabella Pietrantonio, Thomas Goiran, Esther del Cid Pellitero, Jamil Ahmad, Jennifer A. Ruskey, Farnaz Asayesh, Dan Spiegelman, Ziv Gan-Or & Edward A. Fon</p></li><li><p>Department of Neurology and Neurosurgery, McGill University, Montréal, Canada</p><p>Jace Jones-Tabah, Konstantin Senkevich, Yuting Cousineau, Jamil Ahmad, Jennifer A. Ruskey, Oury Monchi, Austen Milnerwood & Edward A. Fon</p></li><li><p>Early Drug Discovery Unit (EDDU), Montreal Neurological Institute-Hospital, McGill University, Montreal, Canada</p><p>Taylor Goldsmith, Carol X.-Q. Chen, Wen Luo, Zhipeng You, Narges Abdian & Thomas M. Durcan</p></li><li><p>Research Department, Bioinformatics Institute, Saint-Petersburg, Russia</p><p>Daria Nikanorova</p></li><li><p>Department of Human Genetics, McGill University, Montréal, Canada</p><p>Farnaz Asayesh & Ziv Gan-Or</p></li><li><p>Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA</p><p>Stanley Fahn, Cheryl Waters & Roy N. Alcalay</p></li><li><p>Département de Radiologie, Radio-Oncologie Et Médecine Nucléaire, Université de Montréal, Montréal, QC, Canada</p><p>Oury Monchi</p></li><li><p>Centre de Recherche de L’Institut Universitaire de Gériatrie de Montréal, Montréal, QC, Canada</p><p>Oury Monchi</p></li><li><p>Sleep Unit, Department of Neurology, National Reference Center for Narcolepsy, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Montpellier, France</p><p>Yves Dauvilliers<","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"11 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849032","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}

{"title":"Aging-associated sensory decline and Alzheimer’s disease","authors":"Suji Hong, Seung-Hyun Baek, Mitchell K. P. Lai, Thiruma V. Arumugam, Dong-Gyu Jo","doi":"10.1186/s13024-024-00776-y","DOIUrl":"https://doi.org/10.1186/s13024-024-00776-y","url":null,"abstract":"Multisensory decline is common as people age, and aging is the primary risk of Alzheimer’s Disease (AD). Recent studies have begun to shed light on the possibility that age-related sensory decline could accelerate AD pathogenesis, or be a prodromal indicator of AD. Sensory impairments, specifically in taste and smell, often emerge before cognitive symptoms in AD, indicating their potential as early biomarkers. Olfactory dysfunction has been frequently associated with AD and may offer valuable insights into early detection. Hearing impairment is significantly associated with AD, but its causal impact on AD progression remains unclear. The review also discusses visual and tactile deficits in AD, including retinal thinning and changes in tactile perception, highlighting their links to disease progression. Focusing on molecular mechanisms, the review explores the roles of amyloid-β (Aβ) accumulation and tau protein pathology in sensory decline and their bidirectional relationship with AD. In summary, the evidence presented conclusively supports advocating for an integrated approach to understanding AD and sensory decline, to enhance early detection, implementing preventive strategies, and developing therapeutic interventions for AD. This approach underscores the significance of sensory health in addressing neurodegenerative diseases, particularly AD.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"82 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763077","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}

{"title":"Seeding activity of skin misfolded tau as a biomarker for tauopathies.","authors":"Zerui Wang, Ling Wu, Maria Gerasimenko, Tricia Gilliland, Zahid Syed Ali Shah, Evalynn Lomax, Yirong Yang, Steven A Gunzler, Vincenzo Donadio, Rocco Liguori, Bin Xu, Wen-Quan Zou","doi":"10.1186/s13024-024-00781-1","DOIUrl":"10.1186/s13024-024-00781-1","url":null,"abstract":"<p><strong>Background: </strong>Tauopathies are a group of age-related neurodegenerative diseases characterized by the accumulation of pathologically hyperphosphorylated tau protein in the brain, leading to prion-like aggregation and propagation. They include Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD). Currently, reliable diagnostic biomarkers that directly reflect the capability of propagation and spreading of misfolded tau aggregates in peripheral tissues and body fluids are lacking.</p><p><strong>Methods: </strong>We utilized the seed-amplification assay (SAA) employing ultrasensitive real-time quaking-induced conversion (RT-QuIC) to assess the prion-like seeding activity of pathological tau in the skin of cadavers with neuropathologically confirmed tauopathies, including AD, PSP, CBD, and PiD, compared to normal controls.</p><p><strong>Results: </strong>We found that the skin tau-SAA demonstrated a significantly higher sensitivity (75-80%) and specificity (95-100%) for detecting tauopathy, depending on the tau substrates used. Moreover, the increased tau-seeding activity was also observed in biopsy skin samples from living AD and PSP patients examined. Analysis of the end products of skin-tau SAA confirmed that the increased seeding activity was accompanied by the formation of tau aggregates with different physicochemical properties related to two different tau substrates used.</p><p><strong>Conclusions: </strong>Overall, our study provides proof-of-concept that the skin tau-SAA can differentiate tauopathies from normal controls, suggesting that the seeding activity of misfolded tau in the skin could serve as a diagnostic biomarker for tauopathies.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"19 1","pages":"92"},"PeriodicalIF":14.9,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11606191/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NOTCH2NLC GGC intermediate repeat with serine induces hypermyelination and early Parkinson's disease-like phenotypes in mice.","authors":"Haitao Tu, Xin Yi Yeo, Zhi-Wei Zhang, Wei Zhou, Jayne Yi Tan, Li Chi, Sook-Yoong Chia, Zhihong Li, Aik Yong Sim, Brijesh Kumar Singh, Dongrui Ma, Zhidong Zhou, Isabelle Bonne, Shuo-Chien Ling, Adeline S L Ng, Sangyong Jung, Eng-King Tan, Li Zeng","doi":"10.1186/s13024-024-00780-2","DOIUrl":"10.1186/s13024-024-00780-2","url":null,"abstract":"<p><strong>Background: </strong>The expansion of GGC repeats (typically exceeding 60 repeats) in the 5' untranslated region (UTR) of the NOTCH2NLC gene (N2C) is linked to N2C-related repeat expansion disorders (NREDs), such as neuronal intranuclear inclusion disease (NIID), frontotemporal dementia (FTD), essential tremor (ET), and Parkinson's disease (PD). These disorders share common clinical manifestations, including parkinsonism, dementia, seizures, and muscle weakness. Intermediate repeat sizes ranging from 40 to 60 GGC repeats, particularly those with AGC-encoded serine insertions, have been reported to be associated with PD; however, the functional implications of these intermediate repeats with serine insertion remain unexplored.</p><p><strong>Methods: </strong>Here, we utilized cellular models harbouring different sizes of N2C variant 2 (N2C2) GGC repeat expansion and CRISPR-Cas9 engineered transgenic mouse models carrying N2C2 GGC intermediate repeats with and without serine insertion to elucidate the underlying pathophysiology associated with N2C intermediate repeat with serine insertion in NREDs.</p><p><strong>Results: </strong>Our findings revealed that the N2C2 GGC intermediate repeat with serine insertion (32G13S) led to mitochondrial dysfunction and cell death in vitro. The neurotoxicity was influenced by the length of the repeat and was exacerbated by the presence of the serine insertion. In 12-month-old transgenic mice, 32G13S intensified intranuclear aggregation and exhibited early PD-like characteristics, including the formation of α-synuclein fibers in the midbrain and the loss of tyrosine hydroxylase (TH)-positive neurons in both the cortex and striatum. Additionally, 32G13S induced neuronal hyperexcitability and caused locomotor behavioural impairments. Transcriptomic analysis of the mouse cortex indicated dysregulation in calcium signaling and MAPK signaling pathways, both of which are critical for mitochondrial function. Notably, genes associated with myelin sheath components, including MBP and MOG, were dysregulated in the 32G13S mouse. Further investigations using immunostaining and transmission electron microscopy revealed that the N2C intermediate repeat with serine induced mitochondrial dysfunction-related hypermyelination in the cortex.</p><p><strong>Conclusions: </strong>Our in vitro and in vivo investigations provide the first evidence that the N2C-GGC intermediate repeat with serine promotes intranuclear aggregation of N2C, leading to mitochondrial dysfunction-associated hypermyelination and neuronal hyperexcitability. These changes contribute to motor deficits in early PD-like neurodegeneration in NREDs.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"19 1","pages":"91"},"PeriodicalIF":14.9,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11603791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human VCP mutant ALS/FTD microglia display immune and lysosomal phenotypes independently of GPNMB","authors":"Benjamin E. Clarke, Oliver J. Ziff, Giulia Tyzack, Marija Petrić Howe, Yiran Wang, Pierre Klein, Claudia A. Smith, Cameron A. Hall, Adel Helmy, Michael Howell, Gavin Kelly, Rickie Patani","doi":"10.1186/s13024-024-00773-1","DOIUrl":"https://doi.org/10.1186/s13024-024-00773-1","url":null,"abstract":"Microglia play crucial roles in maintaining neuronal homeostasis but have been implicated in contributing to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the role of microglia in ALS/FTD remains incompletely understood. Here, we generated highly enriched cultures of VCP mutant microglia derived from human induced pluripotent stem cells (hiPSCs) to investigate their cell autonomous and non-cell autonomous roles in ALS pathogenesis. We used RNA-sequencing, proteomics and functional assays to study hiPSC derived VCP mutant microglia and their effects on hiPSC derived motor neurons and astrocytes. Transcriptomic, proteomic and functional analyses revealed immune and lysosomal dysfunction in VCP mutant microglia. Stimulating healthy microglia with the inflammatory inducer lipopolysaccharide (LPS) showed partial overlap with VCP mutant microglia in their reactive transformation. LPS-stimulated VCP mutant microglia displayed differential activation of inflammatory pathways compared with LPS-stimulated healthy microglia. Conserved gene expression changes were identified between VCP mutant microglia, SOD1 mutant mice microglia, and postmortem ALS spinal cord microglial signatures, including increased expression of the transmembrane glycoprotein GPNMB. While knockdown of GPNMB affected inflammatory and phagocytosis processes in microglia, this was not sufficient to ameliorate cell autonomous phenotypes in VCP mutant microglia. Secreted factors from VCP mutant microglia were sufficient to activate the JAK-STAT pathway in hiPSC derived motor neurons and astrocytes. VCP mutant microglia undergo cell autonomous reactive transformation involving immune and lysosomal dysfunction that partially recapitulate key phenotypes of microglia from other ALS models and post mortem tissue. These phenotypes occur independently of GPNMB. Additionally, VCP mutant microglia elicit non cell autonomous responses in motor neurons and astrocytes involving the JAK-STAT pathway.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"8 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142713202","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}

{"title":"The Parkinson’s disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons","authors":"Jace Jones-Tabah, Kathy He, Nathan Karpilovsky, Konstantin Senkevich, Ghislaine Deyab, Isabella Pietrantonio, Thomas Goiran, Yuting Cousineau, Daria Nikanorova, Taylor Goldsmith, Esther del Cid Pellitero, Carol X.-Q. Chen, Wen Luo, Zhipeng You, Narges Abdian, Jamil Ahmad, Jennifer A. Ruskey, Farnaz Asayesh, Dan Spiegelman, Stanley Fahn, Cheryl Waters, Oury Monchi, Yves Dauvilliers, Nicolas Dupré, Irina Miliukhina, Alla Timofeeva, Anton Emelyanov, Sofya Pchelina, Lior Greenbaum, Sharon Hassin-Baer, Roy N. Alcalay, Austen Milnerwood, Thomas M. Durcan, Ziv Gan-Or, Edward A. Fon","doi":"10.1186/s13024-024-00779-9","DOIUrl":"https://doi.org/10.1186/s13024-024-00779-9","url":null,"abstract":"Variants in the CTSB gene encoding the lysosomal hydrolase cathepsin B (catB) are associated with increased risk of Parkinson’s disease (PD). However, neither the specific CTSB variants driving these associations nor the functional pathways that link catB to PD pathogenesis have been characterized. CatB activity contributes to lysosomal protein degradation and regulates signaling processes involved in autophagy and lysosome biogenesis. Previous in vitro studies have found that catB can cleave monomeric and fibrillar alpha-synuclein, a key protein involved in the pathogenesis of PD that accumulates in the brains of PD patients. However, truncated synuclein isoforms generated by catB cleavage have an increased propensity to aggregate. Thus, catB activity could potentially contribute to lysosomal degradation and clearance of pathogenic alpha synuclein from the cell, but also has the potential of enhancing synuclein pathology by generating aggregation-prone truncations. Therefore, the mechanisms linking catB to PD pathophysiology remain to be clarified. Here, we conducted genetic analyses of the association between common and rare CTSB variants and risk of PD. We then used genetic and pharmacological approaches to manipulate catB expression and function in cell lines, induced pluripotent stem cell-derived dopaminergic neurons and midbrain organoids and assessed lysosomal activity and the handling of aggregated synuclein fibrils. We find that catB inhibition impairs autophagy, reduces glucocerebrosidase (encoded by GBA1) activity, and leads to an accumulation of lysosomal content. In cell lines, reduction of CTSB gene expression impairs the degradation of pre-formed alpha-synuclein fibrils, whereas CTSB gene activation enhances fibril clearance. In midbrain organoids and dopaminergic neurons treated with alpha-synuclein fibrils, catB inhibition potentiates the formation of inclusions which stain positively for phosphorylated alpha-synuclein. These results indicate that the reduction of catB function negatively impacts lysosomal pathways associated with PD pathogenesis, while conversely catB activation could promote the clearance of pathogenic alpha-synuclein.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"183 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142697125","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}

{"title":"A novel AAV Vector for gene therapy of RPE-related retinal degenerative diseases via intravitreal delivery","authors":"Yajun Gong, Xianyu Huang, Tianxiang Tu, Cenfeng Chu, Chunrui Xian, Yushun Yuan, Xin Fu, Ruobi Li, Guisheng Zhong, Xiaolai Zhou","doi":"10.1186/s13024-024-00777-x","DOIUrl":"https://doi.org/10.1186/s13024-024-00777-x","url":null,"abstract":"&lt;p&gt;&lt;b&gt;To the editor&lt;/b&gt;,&lt;/p&gt;&lt;p&gt;Dysfunction of retinal pigment epithelium (RPE) cells leads to multiple blinding retinal degenerative diseases, including retinitis pigmentosa, age-related macular degeneration, and Stargardt disease [1]. Currently, no drug treatments are available to cure or slow the progression of these diseases, and gene therapy has been considered a promising approach. However, when delivered via intravitreal injection, commonly used vectors like AAV2 and AAV9 exhibit poor transduction rates in RPE cells. Subretinal injection, while more effective, requires sophisticated surgical skills and carries risks, such as retinal tears and detachments [2]. Therefore, developing a highly efficient RPE-specific AAV variant for intravitreal injection would be invaluable for gene therapy of RPE-related retinal degenerative diseases.&lt;/p&gt;&lt;p&gt;To identify such an AAV variant, we conducted a multi-round in vivo screening by intravitreal injection in mice with a randomized 9-mer library (diversity of 1.34E6), inserted between positions 587–588 of AAV2 capsid (Fig. 1A). We analyzed NGS data of collected viral genomes from three rounds of screening based on their read counts and enrichment scores, ultimately identifying 10 candidate variants (Supplemental Fig. 1A-I). Preliminary validation in mice revealed a variant with specific transduction for RPE cells, named AAV206 (Supplemental Fig. 1J). We then characterized the transduction properties of AAV206 in detail. Mice received intravitreal injections of AAV2-GFP and AAV206-GFP, and subsequent analysis of whole mounts of the RPE-choroid-sclera complex and retina showed that AAV2-GFP predominantly transduced neuroretinal cells with negligible transduction of RPE cells. In contrast, AAV206-GFP efficiently and specifically transduced RPE cells with minimal neuroretinal transduction (Fig. 1B-D). Consistent with these findings, frozen sections of the retina revealed that AAV2-GFP expression was mainly observed in retinal ganglion cell layer and inner nuclear layer, whereas AAV206-GFP specifically transduced RPE cells (Fig. 1E-F).&lt;/p&gt;&lt;figure&gt;&lt;figcaption&gt;&lt;b data-test=\"figure-caption-text\"&gt;Fig. 1&lt;/b&gt;&lt;/figcaption&gt;&lt;picture&gt;&lt;source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13024-024-00777-x/MediaObjects/13024_2024_777_Fig1_HTML.png?as=webp\" type=\"image/webp\"/&gt;&lt;img alt=\"figure 1\" aria-describedby=\"Fig1\" height=\"894\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13024-024-00777-x/MediaObjects/13024_2024_777_Fig1_HTML.png\" width=\"685\"/&gt;&lt;/picture&gt;&lt;p&gt;A novel RPE-specific AAV vector. &lt;b&gt;(A)&lt;/b&gt; Schematic diagram of AAV vectors screened for specific targeting of RPE cells. &lt;b&gt;(B)&lt;/b&gt; Whole mounts of mice retina and RPE-Choroid-Sclera after intravitreal injection of AAV2-GFP or AAV206-GFP for 14 days. GFP expression (green) indicates positively transduced cells. RPE cells are marked by ZO-1 (red). Scale bar: 1000 μm (left panel), 20 μm (","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"36 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142713089","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}

{"title":"Nuclear pore and nucleocytoplasmic transport impairment in oxidative stress-induced neurodegeneration: relevance to molecular mechanisms in Pathogenesis of Parkinson’s and other related neurodegenerative diseases","authors":"Zainab Riaz, Gabriel S. Richardson, Huajun Jin, Gary Zenitsky, Vellareddy Anantharam, Arthi Kanthasamy, Anumantha G. Kanthasamy","doi":"10.1186/s13024-024-00774-0","DOIUrl":"https://doi.org/10.1186/s13024-024-00774-0","url":null,"abstract":"Nuclear pore complexes (NPCs) are embedded in the nuclear envelope and facilitate the exchange of macromolecules between the nucleus and cytoplasm in eukaryotic cells. The dysfunction of the NPC and nuclear transport plays a significant role in aging and the pathogenesis of various neurodegenerative diseases. Common features among these neurodegenerative diseases, including Parkinson’s disease (PD), encompass mitochondrial dysfunction, oxidative stress and the accumulation of insoluble protein aggregates in specific brain regions. The susceptibility of dopaminergic neurons to mitochondrial stress underscores the pivotal role of mitochondria in PD progression. Disruptions in mitochondrial-nuclear communication are exacerbated by aging and α-synuclein-induced oxidative stress in PD. The precise mechanisms underlying mitochondrial impairment-induced neurodegeneration in PD are still unclear. Evidence suggests that perturbations in dopaminergic neuronal nuclei are linked to PD-related neurodegeneration. These perturbations involve structural damage to the nuclear envelope and mislocalization of pivotal transcription factors, potentially driven by oxidative stress or α-synuclein pathology. The presence of protein aggregates, pathogenic mutations, and ongoing oxidative stress can exacerbate the dysfunction of NPCs, yet this mechanism remains understudied in the context of oxidative stress-induced PD. This review summarizes the link between mitochondrial dysfunction and dopaminergic neurodegeneration and outlines the current evidence for nuclear envelope and nuclear transport abnormalities in PD, particularly in oxidative stress. We highlight the potential role of nuclear pore and nucleocytoplasmic transport dysfunction in PD and stress the importance of systematically investigating NPC components in PD.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"24 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142690838","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}