Acta Neuropathologica Communications最新文献

{"title":"Cystic glioblastoma is associated with alterations of KDR and the Rb pathway: a single-center retrospective analysis.","authors":"Johannes Werner, Sahar Alizada, Cheuk Hong Leung, Heather Lin, Ahmed Msherghi, Erick Campbell, Chetna Wathoo, Chibawanye I Ene, Maria A Gubbiotti, Vinay Puduvalli, Max Wintermark, Nazanin K Majd","doi":"10.1186/s40478-026-02328-5","DOIUrl":"10.1186/s40478-026-02328-5","url":null,"abstract":"<p><p>Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Cystic GBM is a phenotypic subset requiring distinct clinical management. This study aimed to comprehensively assess the genomic landscape of cystic GBM. GBM, IDH wild-type patients with available next-generation sequencing and presurgical brain MRI data were evaluated for cysts by neuroimaging specialists and a senior neuroradiologist. Patients with incomplete radiological or histopathological data, treatment-related cysts, or indeterminate cyst status were excluded. We used logistic regression to assess the association of cystic GBM with demographic variables and the top 24 altered genes. We employed Cox regression to analyze the association of cystic GBM with survival. Among 374 eligible patients, we identified 111 (30%) with cystic GBM and 263 (70%) with non-cystic GBM. Multivariable logistic regression revealed the association of cystic GBM with alterations of the KDR (OR 8.75 [1.77-43.3], p = 0.038), RB1 (OR 5.12 [2.58-10.1], p = 0.008), TP53 (OR 2.72 [1.67-4.43], p = 0.008), CDK4 (OR 2.36 [1.27-4.37], p = 0.036) genes, as well as wild type EGFR (OR 0.33 [0.20-0.53], p = 0.008). Cystic GBM was not associated with overall survival (HR 0.82 [0.61-1.11], p = 0.205). Cystic GBM is marked by alterations of the Rb and p53 pathways as well as KDR alterations. This provides new insights into the pathogenesis of cystic GBM. Several alterations associated with cystic GBM, including CDK4 and KDR, are targets of small-molecule inhibitors. Further research is required to explore the diagnostic and therapeutic implications of this association.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13491840/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148248760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"α-Synuclein overexpression increases the tropism of pre-formed fibrils and MSA-patient derived seeds towards oligodendroglia.","authors":"Anne-Line Strange Laursen, Frida Lind-Holm Mogensen, Jonas Folke, Marie Frederikke Garnæs, Luisa Harriet Knecht, Tomasz Brudek, Mikkel Vestergaard Olesen, Marlene Bidstrup, Sanne S Kaalund, Susanne Holst-Williams, Katarina Willén, Michelle Pinho, Sandra Pritzkow, Alexander K Buell, Azad Farzadfard, Claudio Soto, Karina Fog, Louise Torp Dalgaard, Florence Sotty, Susana Aznar","doi":"10.1186/s40478-026-02346-3","DOIUrl":"10.1186/s40478-026-02346-3","url":null,"abstract":"<p><p>Multiple system atrophy (MSA) is a rare, fatal neurodegenerative disease, pathologically characterized by glial cytoplasmic inclusions (GCIs) containing α-synuclein (αSyn). The causes leading to aberrant αSyn accumulation in oligodendroglia remain unknown. Recent evidence of increased αSyn mRNA in GCI-bearing oligodendrocytes suggests that oligodendroglia αSyn expression may be a key determinant of GCI formation. To ascertain this, we generated a new transgenic (TG) mouse line overexpressing human (h-) αSyn through the myelin basic protein promoter (MBP-hSNCA mice). Immunofluorescence combined with machine learning-based classification confirmed age-independent oligodendroglial αSyn localization, with no evidence of aggregated and pathological αSyn, as assessed by a FRET-based assay, biochemical fractionation, and the seed amplification assay (SAA). Upon intrastriatal inoculation of hαSyn preformed fibrils (hPFFs), the fraction of oligodendroglial αSyn positive insoluble aggregates increased over time in TG compared to wildtype (WT) mice, reaching significance six to nine months after inoculation. This was accompanied by an increase in brain αSyn seeding potency. As proof of concept, we investigated whether preferential oligodendroglia vulnerability is influenced by intrinsic fibril potency by intrastriatally injecting TG and WT mice with αSyn fibrils amplified from 2 MSA or 1 PD patient's brains. Six months post inoculation, MSA-inoculated brains retained the MSA-characteristic seeding profile and exhibited higher seeding potency compared to PD-inoculated mice. TG mice showed significantly more widespread phosphorylated αSyn (pSyn) pathology than WT, independent of whether they were seeded with MSA- or PD-fibrils. However, oligodendroglial inclusions were significantly more abundant in TG mice injected with MSA-derived αSyn. In conclusion, our results indicate that intracellular αSyn expression facilitates the development of oligodendroglial pathology, supporting the hypothesis that increased αSyn expression may represent a rate-limiting step in GCI formation.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13491732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148248797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spinal low-grade ependymal tumors harboring telomerase reverse transcriptase promoter mutation and chromosome 7 gain with methylation profile of spinal subependymoma.","authors":"Yoshitaka Nagashima, Junya Yamaguchi, Yusuke Nishimura, Masafumi Seki, Seiji Yamada, Sachi Maeda, Eisuke Tsukamoto, Ryo Yamamoto, Yuhei Takido, Keisuke Kimura, Fumiharu Ohka, Kennosuke Karube, Ryuta Saito","doi":"10.1186/s40478-026-02334-7","DOIUrl":"10.1186/s40478-026-02334-7","url":null,"abstract":"<p><p>Spinal intramedullary tumors comprise a heterogeneous group of entities with diverse histopathological features, making their diagnosis particularly challenging. With the introduction of DNA methylation profiling, the underlying biological diversity of these tumors has been increasingly clarified and systematized; however, owing to the rarity of these tumors, case accumulation remains limited, and significant challenges persist. In this study, we identified two cases of spinal ependymal tumors exhibiting a methylation profile of spinal (SP-) subependymoma (SEPN). Both cases occurred in elderly patients and demonstrated circumscribed growth consistent with low-grade ependymal tumors; however, these tumors did not exhibit the typical histopathological features required for a diagnosis of SEPN in the 2021 WHO classification of central nervous system (CNS) tumors, showing indistinct cluster formation, an astrocytic immunohistochemical profile suggested by Olig2 expression, and relatively elevated Ki-67 labeling indices of 4.5% and 3.1%. At the molecular level, both cases harbored telomerase reverse transcriptase promoter mutations and whole chromosome 7 gain. On two-dimensional t-distributed stochastic neighbor embedding analysis, both clustered within the SP-SEPN methylation class at its periphery, with low classifier calibration scores (0.70 and 0.69). According to the current WHO classification, these cases are designated as low-grade ependymal tumors (CNS WHO grade 2) with methylation profile of SP-SEPN because they do not meet the essential WHO histopathological criteria. Ependymal tumors exhibiting a methylation profile consistent with SEPN, but discordant histopathological features have been increasingly recognized, and the appropriate classification of such tumors remains a subject of ongoing debate. These cases provide important insights into the histopathological diversity of ependymal tumors and contribute to establishing a more comprehensive and systematic classification of ependymal tumors.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13491719/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148248788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: MRC1 and LYVE1 expressing macrophages in vascular beds of GNAQ p.R183Q driven capillary malformations in Sturge Weber syndrome.","authors":"Sana Nasim, Colette Bichsel, Stephen Dayneka, Robert Mannix, Annegret Holm, Mathew Vivero, Sanda Alexandrescu, Anna Pinto, Arin K Greene, Donald E Ingber, Joyce Bischoff","doi":"10.1186/s40478-026-02326-7","DOIUrl":"10.1186/s40478-026-02326-7","url":null,"abstract":"","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"14 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13263957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148238591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low-intensity transcranial ultrasound stimulation suppresses abnormal neural oscillations in the motor cortex by stimulating STN in α-synuclein^A53T mice.","authors":"Qianqian Wang, Shuxun Dong, Zhe Zhao, Zhenfang Ma, Xiaoli Li, Jiaqing Yan, Yi Yuan","doi":"10.1186/s40478-026-02344-5","DOIUrl":"10.1186/s40478-026-02344-5","url":null,"abstract":"<p><p>Previous studies have shown that low-intensity transcranial ultrasound stimulation (TUS) of the subthalamic nucleus (STN) in mice with Parkinson's disease (PD) effectively suppresses pathological discharge activities in motor cortex. However, how TUS modulates the neural activity of the STN-motor cortex circuits, and the long-term effects of suppressing abnormal neural oscillations in α-synuclein^A53T (α-syn) mice remain unclear. Here, we conducted STN-targeted ultrasound in α-syn mice, and examined the treatment efficacy via behavior test and electrophysiology in vivo. Alterations in neural activity patterns were specifically assessed in α-syn mice during pre- and post-therapeutic interventions. We found that TUS targeted at STN significantly (1) ameliorated abnormal neural activity in the STN, (2) reduced the neural correlation between STN and motor cortex, and (3) improved locomotor capability in α-syn mice. Thus, our results demonstrated that STN-targeted TUS rebalanced the neural activity in STN-motor cortex circuit, which was causally linked to the improvement of motor function in α-syn transgenic mice.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13480255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148222435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Soluble α-synuclein oligomers drive transient corticostriatal pathology and delayed nigral vulnerability in a mouse model of early α-synucleinopathy.","authors":"Anna Wilkaniec, Grzegorz A Czapski, Magdalena Cieślik, Gabriela Olech-Kochańczyk, Elżbieta Gawinek, Ewelina Bielska, Eva D Ruiz-Ortega, Lidia Babiec, Marcin Strawski, Piotr Wójcik, Carsten Culmsee, Agata Adamczyk","doi":"10.1186/s40478-026-02340-9","DOIUrl":"10.1186/s40478-026-02340-9","url":null,"abstract":"<p><p>α-Synucleinopathies display pronounced heterogeneity in the spatial distribution of α-synuclein (αSyn) pathology and clinical progression. Although distinct αSyn assemblies-from monomers and soluble oligomers to fibrils-exert non-equivalent biological effects, in vivo studies have predominantly focused on preformed fibrils (PFFs), leaving the pathogenic potential of soluble oligomers insufficiently explored. Here, we investigated the spatiotemporal, molecular, and behavioral consequences of striatal delivery of structurally validated αSyn oligomers in adult mice. Three-month-old male C57BL/6 J mice received bilateral injections of αSyn oligomers into the dorsal caudate-putamen and were analyzed at 30, 90, and 180 days post-injection (dpi) using molecular, histological, and behavioral approaches. αSyn oligomers induced a highly dynamic and region-specific pathological cascade. At 30 dpi, widespread inclusions were evident in cortical and limbic regions projecting to the striatum, followed by a progressive redistribution of pathology toward the striatum at later stages, while inclusions were consistently absent from the substantia nigra pars compacta. In parallel, αSyn oligomers elicited distinct spatiotemporal patterns of inflammatory and oxidative responses across brain regions, characterized by an immediate pro-inflammatory cytokine surge in the striatum, early but transient oxidative response in the cortex and delayed, sustained oxidative stress in the midbrain. Despite modest nigrostriatal degeneration and preserved gross motor performance, sensitive behavioral measures revealed early and persistent motor weakness, suggesting synaptic and axonal dysfunction rather than neuronal loss. Collectively, our findings provide the first in vivo evidence that soluble αSyn oligomers act as potent yet transient drivers of a distributed and partially reversible neuropathological program fundamentally distinct from canonical PFF-based models. By uncovering an oligomer-specific mode of αSyn-induced neurodegeneration, this work demonstrates that disease-relevant pathology can arise from dynamic, regionally uncoupled processes rather than stable fibrillar inclusions, redefining early α-synucleinopathy as a state of selective circuit vulnerability and revealing a previously unrecognized therapeutic window for intervention.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13479984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148215843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulation of complement at the synapse in P301S mice and human tauopathies.","authors":"Jacqui Nimmo, Nikoleta Daskoulidou, Sophie Van Pottelberge, Louis De Muynck, B Paul Morgan","doi":"10.1186/s40478-026-02347-2","DOIUrl":"10.1186/s40478-026-02347-2","url":null,"abstract":"<p><p>Synapse loss is the best correlate of cognitive decline in neurodegenerative diseases (NDDs). In Alzheimer's disease complement dysregulation, triggered by amyloid-β accumulation, plays a major role in synapse loss, but its contribution in other NDDs where amyloid is absent, most notably tauopathies, is elusive. Aggregation of tau is a prominent co-pathology in many NDDs and is characteristic of classical tauopathies in which amyloid pathology is lacking. Here we explore the effect of tau accumulation on complement dysregulation and its contribution to neuronal damage and synapse loss in a mouse tauopathy model harbouring the familial P301S tau mutation and post-mortem brain samples from human tauopathies. Complement gene and protein expression were analysed in P301S mice at 2, 4 and 6 M of age. Complement dysregulation was evident from qPCR analysis showing increased classical pathway (C4, C2), and complement receptor (C3ar1, Cd11b, Cd11c) gene expression in P301S mice compared to wildtype (WT). C1q protein levels were markedly increased in brain homogenates from P301S mice compared to WT, accompanied by C1q deposition on tau aggregates. Synapse loss was evident for both excitatory and inhibitory synapses and was accompanied by an increased percentage of C1q positive excitatory synapses, unaffected by proximity to tau aggregates. The classic pathway regulator CSMD1 was present on synapses and decreased on C1q positive synapses in P301S mice, implying a loss of protection from complement attack. Observations in human tauopathy brains demonstrated decreased CSMD1-labelled excitatory synapses, consistent with findings in P301S mice. These findings demonstrate that complement dysregulation occurs in areas of tau pathology and may contribute to synapse loss in tauopathies.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13495216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148215901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing heme synthesis attenuates pathological α-synuclein propagation in vivo.","authors":"Masami Masuda-Suzukake, Masato Hasegawa, Takashi Nonaka","doi":"10.1186/s40478-026-02336-5","DOIUrl":"10.1186/s40478-026-02336-5","url":null,"abstract":"<p><p>Intraneuronal α-synuclein (αS) accumulation is a central event in the pathogenesis of Parkinson's disease and dementia with Lewy bodies. The spread of αS pathology throughout the central nervous system contributes to disease progression via seed-dependent propagation, yet disease-modifying therapies remain unavailable. We previously reported that porphyrin compounds inhibit αS aggregation in vitro; however, because of their high molecular weight, porphyrins poorly penetrate the blood-brain barrier (BBB). Heme, a porphyrin derivative, is synthesized from 5-aminolevulinic acid (5-ALA) via the heme biosynthetic pathway. In this study, we investigated whether 5-ALA modulates αS accumulation and propagation. Although porphyrin compounds inhibited αS seeding in vitro, 5-ALA itself did not. However, treatment of mouse primary neurons with 5-ALA enhanced heme synthesis and suppressed seed-dependent αS aggregation, suggesting a potential role for intracellular heme in modulating αS propagation. We further evaluated the effects of 5-ALA in an in vivo αS propagation model. Preformed αS fibrils were unilaterally injected into the striatum of wild-type mice, followed by oral administration of 5-ALA at three doses (0, 1.7, and 20 mg/kg/day) for 4 weeks. Biochemical analyses demonstrated that 5-ALA significantly reduced the propagation of sarkosyl-insoluble αS to the contralateral hemisphere. Immunohistochemical analyses revealed a marked reduction in phosphorylated αS pathology in the amygdala and substantia nigra in the 5-ALA-treated groups. Collectively, these findings indicate that oral administration of 5-ALA suppresses αS propagation in vivo, potentially through enhancement of intracellular heme synthesis. Modulation of the heme biosynthetic pathway may represent a novel therapeutic strategy for synucleinopathies.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13465251/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148203621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Age-dependent vascular and neurological characteristics of CADASIL are recapitulated in Notch3 mutant zebrafish, implicating a role for type IV collagen in disease progression.","authors":"Tohgo Kanoh, Shiho Oubayashi, Kengo Furukawa, Kosuke Fujimoto, Amane Inoue, Takamasa Mizoguchi, Masashi Yamaguchi, Azusa Takahashi-Nakaguchi, Yoshinori Hasegawa, Osamu Ohara, Ichio Aoki, Motoyuki Itoh","doi":"10.1186/s40478-026-02333-8","DOIUrl":"10.1186/s40478-026-02333-8","url":null,"abstract":"<p><p>CADASIL is a hereditary cerebral small vessel disease caused by NOTCH3 mutations, leading to age-dependent vascular and neurological impairments. Despite its clinical impact, the underlying pathogenic mechanisms remain poorly understood, partly because existing murine models often fail to fully replicate the broad pathological spectrum observed in humans. Here, we established and characterized a novel zebrafish (Danio rerio) model carrying the Notch3 p.C680S mutation. Our mutant zebrafish mimicked key age-related CADASIL features, including cerebrovascular dysfunction, telencephalic atrophy, cognitive impairment, and the deposition of granular osmiophilic material (GOM). Integrated transcriptomic and proteomic analyses revealed a significant downregulation of type IV collagen-related molecules, including serpinh1b, col4a1, and col4a2. These molecular findings were corroborated by immunostaining, which confirmed reduced perivascular accumulation of type IV collagen around cerebral blood vessels. Furthermore, AlphaFold 3-based structural modeling categorized the p.C680S variant as a \"nonconventional\" NOTCH3 mutation. These findings validate the zebrafish as a valuable vertebrate model for CADASIL and raise the possibility that diminished type IV collagen levels contribute to CADASIL pathogenesis, particularly in cases of nonconventional NOTCH3 mutations.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13455480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148154782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polymeric lysosome-targeting chimeras for extracellular α-synuclein degradation in Parkinson's disease.","authors":"Arghya Bhattacharya, Hailah M Almohaimeed, Waheeb Sami Aggad, Amany I Almars, Osama Mohammed Abdulaziz Altowaijri, Hadeel Abdulrahman Waggas, Nuha M Bauthman, Zuhair M Mohammedsaleh, Tahani Ahmad ALMatrafi, Fayez M Saleh, Daniel Ejim Uti","doi":"10.1186/s40478-026-02335-6","DOIUrl":"10.1186/s40478-026-02335-6","url":null,"abstract":"<p><p>Disease progression in Parkinson's disease has been driven by extracellular α-synuclein prion-like seeding throughout the course of the disease and therefore not just by the intracellular accumulation of the protein in isolated aggregates. Current therapies utilizing PROTACs cannot address the extra-cellular effects of α-synuclein spreading in this manner. This article proposes PolyTACs (Polymeric Lysosome-Targeting Chimeras) as hybrid antibody-polymer conjugates which use neuronal exofacial thiol groups produced because of DJ-1/GSH dysregulation to capture α-synuclein pathological conformers before they can be derepressed (seeded pathological aggregates) into the cytoplasm. The hybridity of these antibodies (oligomers and fibrils) combined with pyridyl disulfide linkages in the multi-valent polymer allows these compounds to circumvent LTR co-option, and to be trafficked to lysosomes via a non-clathrin pathway. The delivery route for these agents is intended to be via intra-nasal, thereby bypassing many of the issues associated with delivery through the BBB. Delivery to patients will be guided by thiol profiling in cerebrospinal fluid to assist in inclusion-exclusion criteria for patients in prodromal trials. With these developments, it is anticipated that this new class of agent may provide a modular framework adaptable to other proteinopathies such as tau and TDP-43, pending further validation.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148148012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}