Acta Neuropathologica最新文献

{"title":"Pure LATE-NC: Frequency, clinical impact, and the importance of considering APOE genotype when assessing this and other subtypes of non-Alzheimer’s pathologies","authors":"Yuriko Katsumata,&nbsp;Xian Wu,&nbsp;Khine Zin Aung,&nbsp;David W. Fardo,&nbsp;Davis C. Woodworth,&nbsp;S. Ahmad Sajjadi,&nbsp;Sandra O. Tomé,&nbsp;Dietmar Rudolf Thal,&nbsp;Juan C. Troncoso,&nbsp;Koping Chang,&nbsp;Charles Mock,&nbsp;Peter T. Nelson","doi":"10.1007/s00401-024-02821-y","DOIUrl":"10.1007/s00401-024-02821-y","url":null,"abstract":"<div><p>Pure limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (pure LATE-NC) is a term used to describe brains with LATE-NC but lacking intermediate or severe levels of Alzheimer’s disease neuropathologic changes (ADNC). Focusing on pure LATE-NC, we analyzed data from the National Alzheimer’s Coordinating Center (NACC) Neuropathology Data Set, comprising clinical and pathological information aggregated from 32 NIH-funded Alzheimer’s Disease Research Centers (ADRCs). After excluding subjects dying with unusual conditions, n = 1,926 autopsied subjects were included in the analyses. For &gt; 90% of these participants, apolipoprotein E (<i>APOE)</i> allele status was known; 46.5% had at least one <i>APOE</i> 4 allele. In most human populations, only 15–25% of people are <i>APOE</i> ε4 carriers. ADRCs with higher documented AD risk allele (<i>APOE</i> or <i>BIN1</i>) rates had fewer participants lacking ADNC, and correspondingly low rates of pure LATE-NC. Among <i>APOE</i> ε4 non-carries, 5.3% had pure LATE-NC, 37.0% had pure ADNC, and 3.6% had pure neocortical Lewy body pathology. In terms of clinical impact, participants with pure LATE-NC tended to die after having received a diagnosis of dementia: 56% died with dementia among <i>APOE</i> ε4 non-carrier participants, comparable to 61% with pure ADNC. LATE-NC was associated with increased Clinical Dementia Rating Sum of Boxes (CDR-SOB) scores, i.e. worsened global cognitive impairments, in participants with no/low ADNC and no neocortical Lewy body pathology (p = 0.0023). Among pure LATE-NC cases, there was a trend for higher LATE-NC stages to be associated with worse CDR-SOB scores (p = 0.026 for linear trend of LATE-NC stages). Pure LATE-NC was not associated with clinical features of disinhibition or primary progressive aphasia. In summary, LATE-NC with no or low levels of ADNC was less frequent than pure ADNC but was not rare, particularly among individuals who lacked the <i>APOE</i> 4 allele, and in study cohorts with <i>APOE</i> 4 frequencies similar to those in most human populations.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02821-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637182","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":"Microglia contribute to the production of the amyloidogenic ABri peptide in familial British dementia","authors":"Charles Arber,&nbsp;Jackie M. Casey,&nbsp;Samuel Crawford,&nbsp;Naiomi Rambarack,&nbsp;Umran Yaman,&nbsp;Sarah Wiethoff,&nbsp;Emma Augustin,&nbsp;Thomas M. Piers,&nbsp;Matthew Price,&nbsp;Agueda Rostagno,&nbsp;Jorge Ghiso,&nbsp;Patrick A. Lewis,&nbsp;Tamas Revesz,&nbsp;John Hardy,&nbsp;Jennifer M. Pocock,&nbsp;Henry Houlden,&nbsp;Jonathan M. Schott,&nbsp;Dervis A. Salih,&nbsp;Tammaryn Lashley,&nbsp;Selina Wray","doi":"10.1007/s00401-024-02820-z","DOIUrl":"10.1007/s00401-024-02820-z","url":null,"abstract":"<div><p>Mutations in <i>ITM2B</i> cause familial British, Danish, Chinese, and Korean dementias. In familial British dementia (FBD), a mutation in the stop codon of the <i>ITM2B</i> gene (also known as <i>BRI2</i>) causes a C-terminal cleavage fragment of the ITM2B/BRI2 protein to be extended by 11 amino acids. This fragment, termed amyloid-Bri (ABri), is highly insoluble and forms extracellular plaques in the brain. ABri plaques are accompanied by tau pathology, neuronal cell death and progressive dementia, with striking parallels to the aetiology and pathogenesis of Alzheimer’s disease. The molecular mechanisms underpinning FBD are ill-defined. Using patient-derived induced pluripotent stem cells, we show that expression of <i>ITM2B/BRI2</i> is 34-fold higher in microglia than neurons and 15-fold higher in microglia compared with astrocytes. This cell-specific enrichment is supported by expression data from both mouse and human brain tissue. ITM2B/BRI2 protein levels are higher in iPSC-microglia compared with neurons and astrocytes. The ABri peptide was detected in patient iPSC-derived microglial lysates and conditioned media but was undetectable in patient-derived neurons and control microglia. The pathological examination of post-mortem tissue supports the presence of ABri in microglia that are in proximity to pre-amyloid deposits. Finally, gene co-expression analysis supports a role for ITM2B/BRI2 in disease-associated microglial responses. These data demonstrate that microglia are major contributors to the production of amyloid forming peptides in FBD, potentially acting as instigators of neurodegeneration. Additionally, these data also suggest ITM2B/BRI2 may be part of a microglial response to disease, motivating further investigations of its role in microglial activation. These data have implications for our understanding of the role of microglia and the innate immune response in the pathogenesis of FBD and other neurodegenerative dementias including Alzheimer’s disease.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02820-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142636668","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":"Correction: Multiciliated ependymal cells: an update on biology and pathology in the adult brain","authors":"Adam M. R. Groh,&nbsp;Yeji Lori Song,&nbsp;Fiona Tea,&nbsp;Brianna Lu,&nbsp;Stephanie Huynh,&nbsp;Elia Afanasiev,&nbsp;Maxime Bigotte,&nbsp;Marc R. Del Bigio,&nbsp;Jo Anne Stratton","doi":"10.1007/s00401-024-02826-7","DOIUrl":"10.1007/s00401-024-02826-7","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611885","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":"No sex difference in the extent of acute mechanical blood–brain barrier disruption after experimental concussion","authors":"Hailong Song,&nbsp;Eashwar Kantemneni,&nbsp;Yue Qiu,&nbsp;Jean-Pierre Dolle,&nbsp;D. Kacy Cullen,&nbsp;William Stewart,&nbsp;Douglas H. Smith","doi":"10.1007/s00401-024-02829-4","DOIUrl":"10.1007/s00401-024-02829-4","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611886","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":"Transcriptome analysis stratifies second-generation non-WNT/non-SHH medulloblastoma subgroups into clinically tractable subtypes","authors":"Andrey Korshunov,&nbsp;Konstantin Okonechnikov,&nbsp;Daniel Schrimpf,&nbsp;Svenja Tonn,&nbsp;Martin Mynarek,&nbsp;Jan Koster,&nbsp;Philipp Sievers,&nbsp;Till Milde,&nbsp;Felix Sahm,&nbsp;David T. W. Jones,&nbsp;Andreas von Deimling,&nbsp;Stefan M. Pfister,&nbsp;Marcel Kool","doi":"10.1007/s00401-023-02575-z","DOIUrl":"10.1007/s00401-023-02575-z","url":null,"abstract":"<div><p>Medulloblastoma (MB), one of the most common malignant pediatric brain tumor, is a heterogenous disease comprised of four distinct molecular groups (WNT, SHH, Group 3, Group 4). Each of these groups can be further subdivided into second-generation MB (SGS MB) molecular subgroups, each with distinct genetic and clinical characteristics. For instance, non-WNT/non-SHH MB (Group 3/4) can be subdivided molecularly into eight distinct and clinically relevant tumor subgroups. A further molecular stratification/summarization of these SGS MB would allow for the assignment of patients to risk-associated treatment protocols. Here, we performed DNA- and RNA-based analysis of 574 non-WNT/non-SHH MB and analyzed the clinical significance of various molecular patterns within the entire cohort and the eight SGS MB, with the aim to develop an optimal risk stratification of these tumors. Multigene analysis disclosed several survival-associated genes highly specific for each molecular subgroup within this non-WNT/non-SHH MB cohort with minimal inter-subgroup overlap. These subgroup-specific and prognostically relevant genes were associated with pathways that could underlie SGS MB clinical-molecular diversity and tumor-driving mechanisms. By combining survival-associated genes within each SGS MB, distinct metagene sets being appropriate for their optimal risk stratification were identified. Defined subgroup-specific metagene sets were independent variables in the multivariate models generated for each SGS MB and their prognostic value was confirmed in a completely non-overlapping validation cohort of non-WNT/non-SHH MB (<i>n</i> = 377). In summary, the current results indicate that the integration of transcriptome data in risk stratification models may improve outcome prediction for each non-WNT/non-SHH SGS MB. Identified subgroup-specific gene expression signatures could be relevant for clinical implementation and survival-associated metagene sets could be adopted for further SGS MB risk stratification. Future studies should aim at validating the prognostic role of these transcriptome-based SGS MB subtypes in prospective clinical trials.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"145 6","pages":"829 - 842"},"PeriodicalIF":12.7,"publicationDate":"2023-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-023-02575-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9501692","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":"Molecular integrators of stress and aging: the example of FKBP5","authors":"Anthony S. Zannas","doi":"10.1007/s00401-023-02572-2","DOIUrl":"10.1007/s00401-023-02572-2","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"145 6","pages":"713 - 715"},"PeriodicalIF":12.7,"publicationDate":"2023-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9536229","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":"Clinical applicability of miR517a detection in liquid biopsies of ETMR patients","authors":"Sibylle Madlener,&nbsp;Julia Furtner,&nbsp;Natalia Stepien,&nbsp;Daniel Senfter,&nbsp;Lisa Mayr,&nbsp;Maximilian Zeyda,&nbsp;Leon Gramss,&nbsp;Barbara Aistleitner,&nbsp;Sabine Spiegl-Kreinecker,&nbsp;Elisa Rivelles,&nbsp;Christian Dorfer,&nbsp;Karl Rössler,&nbsp;Thomas Czech,&nbsp;Amedeo A. Azizi,&nbsp;Andreas Peyrl,&nbsp;Daniela Lötsch-Gojo,&nbsp;Leonhard Müllauer,&nbsp;Christine Haberler,&nbsp;Irene Slavc,&nbsp;Johannes Gojo","doi":"10.1007/s00401-023-02567-z","DOIUrl":"10.1007/s00401-023-02567-z","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"145 6","pages":"843 - 846"},"PeriodicalIF":12.7,"publicationDate":"2023-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-023-02567-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9542516","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":"Molecular characterisation defines clinically-actionable heterogeneity within Group 4 medulloblastoma and improves disease risk-stratification","authors":"Jack Goddard,&nbsp;Jemma Castle,&nbsp;Emily Southworth,&nbsp;Anya Fletcher,&nbsp;Stephen Crosier,&nbsp;Idoia Martin-Guerrero,&nbsp;Miguel García-Ariza,&nbsp;Aurora Navajas,&nbsp;Julien Masliah-Planchon,&nbsp;Franck Bourdeaut,&nbsp;Christelle Dufour,&nbsp;Olivier Ayrault,&nbsp;Tobias Goschzik,&nbsp;Torsten Pietsch,&nbsp;Martin Sill,&nbsp;Stefan M. Pfister,&nbsp;Stefan Rutkowski,&nbsp;Stacey Richardson,&nbsp;Rebecca M. Hill,&nbsp;Daniel Williamson,&nbsp;Simon Bailey,&nbsp;Edward C. Schwalbe,&nbsp;Steven C. Clifford,&nbsp;Debbie Hicks","doi":"10.1007/s00401-023-02566-0","DOIUrl":"10.1007/s00401-023-02566-0","url":null,"abstract":"<div><p>Group 4 tumours (MB_Grp4) represent the majority of non-WNT/non-SHH medulloblastomas. Their clinical course is poorly predicted by current risk-factors. MB_Grp4 molecular substructures have been identified (e.g. subgroups/cytogenetics/mutations), however their inter-relationships and potential to improve clinical sub-classification and risk-stratification remain undefined. We comprehensively characterised the paediatric MB_Grp4 molecular landscape and determined its utility to improve clinical management. A clinically-annotated discovery cohort (n = 362 MB_Grp4) was assembled from UK-CCLG institutions and SIOP-UKCCSG-PNET3, HIT-SIOP-PNET4 and PNET HR + 5 clinical trials. Molecular profiling was undertaken, integrating driver mutations, second-generation non-WNT/non-SHH subgroups (1–8) and whole-chromosome aberrations (WCAs). Survival models were derived for patients ≥ 3 years of age who received contemporary multi-modal therapies (n = 323). We first independently derived and validated a favourable-risk WCA group (WCA-FR) characterised by ≥ 2 features from chromosome 7 gain, 8 loss, and 11 loss. Remaining patients were high-risk (WCA-HR). Subgroups 6 and 7 were enriched for WCA-FR (p &lt; 0·0001) and aneuploidy. Subgroup 8 was defined by predominantly balanced genomes with isolated isochromosome 17q (p &lt; 0·0001). While no mutations were associated with outcome and overall mutational burden was low, WCA-HR harboured recurrent chromatin remodelling mutations (p = 0·007). Integration of methylation and WCA groups improved risk-stratification models and outperformed established prognostication schemes. Our MB_Grp4 risk-stratification scheme defines: favourable-risk (non-metastatic disease and (i) subgroup 7 or (ii) WCA-FR (21% of patients, 5-year PFS 97%)), very-high-risk (metastatic disease with WCA-HR (36%, 5-year PFS 49%)) and high-risk (remaining patients; 43%, 5-year PFS 67%). These findings validated in an independent MB_Grp4 cohort (n = 668). Importantly, our findings demonstrate that previously established disease-wide risk-features (i.e. LCA histology and <i>MYC(N)</i> amplification) have little prognostic relevance in MB_Grp4 disease. Novel validated survival models, integrating clinical features, methylation and WCA groups, improve outcome prediction and re-define risk-status for ~ 80% of MB_Grp4. Our MB_Grp4 favourable-risk group has MB_WNT-like excellent outcomes, thereby doubling the proportion of medulloblastoma patients who could benefit from therapy de-escalation approaches, aimed at reducing treatment induced late-effects while sustaining survival outcomes. Novel approaches are urgently required for the very-high-risk patients.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"145 5","pages":"651 - 666"},"PeriodicalIF":12.7,"publicationDate":"2023-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-023-02566-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9336943","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":"C-terminal frameshift variant of TDP-43 with pronounced aggregation-propensity causes rimmed vacuole myopathy but not ALS/FTD","authors":"Pedro Ervilha Pereira,&nbsp;Nika Schuermans,&nbsp;Antoon Meylemans,&nbsp;Pontus LeBlanc,&nbsp;Lauren Versluys,&nbsp;Katie E. Copley,&nbsp;Jack D. Rubien,&nbsp;Christopher Altheimer,&nbsp;Myra Peetermans,&nbsp;Elke Debackere,&nbsp;Olivier Vanakker,&nbsp;Sandra Janssens,&nbsp;Jonathan Baets,&nbsp;Kristof Verhoeven,&nbsp;Martin Lammens,&nbsp;Sofie Symoens,&nbsp;Boel De Paepe,&nbsp;Sami J. Barmada,&nbsp;James Shorter,&nbsp;Jan L. De Bleecker,&nbsp;Elke Bogaert,&nbsp;Bart Dermaut","doi":"10.1007/s00401-023-02565-1","DOIUrl":"10.1007/s00401-023-02565-1","url":null,"abstract":"<div><p>Neuronal TDP-43-positive inclusions are neuropathological hallmark lesions in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Pathogenic missense variants in <i>TARDBP</i>, the gene encoding TDP-43, can cause ALS and cluster in the C-terminal prion-like domain (PrLD), where they modulate the liquid condensation and aggregation properties of the protein. TDP-43-positive inclusions are also found in rimmed vacuole myopathies, including sporadic inclusion body myositis, but myopathy-causing TDP-43 variants have not been reported. Using genome-wide linkage analysis and whole exome sequencing in an extended five-generation family with an autosomal dominant rimmed vacuole myopathy, we identified a conclusively linked frameshift mutation in TDP-43 producing a C-terminally altered PrLD (TDP-43^{p.Trp385IlefsTer10}) (maximum multipoint LOD-score 3.61). Patient-derived muscle biopsies showed TDP-43-positive sarcoplasmic inclusions, accumulation of autophagosomes and transcriptomes with abnormally spliced sarcomeric genes (including <i>TTN</i> and <i>NEB</i>) and increased expression of muscle regeneration genes. In vitro phase separation assays demonstrated that TDP-43^{Trp385IlefsTer10} does not form liquid-like condensates and readily forms solid-like fibrils indicating increased aggregation propensity compared to wild-type TDP-43. In <i>Drosophila</i> TDP-43^{p.Trp385IlefsTer10} behaved as a partial loss-of-function allele as it was able to rescue the <i>TBPH</i> (fly ortholog of <i>TARDBP</i>) neurodevelopmental lethal null phenotype while showing strongly reduced toxic gain-of-function properties upon overexpression. Accordingly, TDP-43^{p.Trp385IlefsTer10} showed reduced toxicity in a primary rat neuron disease model. Together, these genetic, pathological, in vitro and in vivo results demonstrate that TDP-43^{p.Trp385IlefsTer10} is an aggregation-prone partial loss-of-function variant that causes autosomal dominant vacuolar myopathy but not ALS/FTD. Our study genetically links TDP-43 proteinopathy to myodegeneration, and reveals a tissue-specific role of the PrLD in directing pathology.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"145 6","pages":"793 - 814"},"PeriodicalIF":12.7,"publicationDate":"2023-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-023-02565-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9561024","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":"Urinary tract infections trigger synucleinopathy via the innate immune response","authors":"Wouter Peelaerts,&nbsp;Gabriela Mercado,&nbsp;Sonia George,&nbsp;Marie Villumsen,&nbsp;Alysa Kasen,&nbsp;Miguel Aguileta,&nbsp;Christian Linstow,&nbsp;Alexandra B. Sutter,&nbsp;Emily Kuhn,&nbsp;Lucas Stetzik,&nbsp;Rachel Sheridan,&nbsp;Liza Bergkvist,&nbsp;Lindsay Meyerdirk,&nbsp;Allison Lindqvist,&nbsp;Martha L. Escobar Gavis,&nbsp;Chris Van den Haute,&nbsp;Scott J. Hultgren,&nbsp;Veerle Baekelandt,&nbsp;J. Andrew Pospisilik,&nbsp;Tomasz Brudek,&nbsp;Susana Aznar,&nbsp;Jennifer A. Steiner,&nbsp;Michael X. Henderson,&nbsp;Lena Brundin,&nbsp;Magdalena I. Ivanova,&nbsp;Tom J. Hannan,&nbsp;Patrik Brundin","doi":"10.1007/s00401-023-02562-4","DOIUrl":"10.1007/s00401-023-02562-4","url":null,"abstract":"<div><p>Symptoms in the urogenital organs are common in multiple system atrophy (MSA), also in the years preceding the MSA diagnosis. It is unknown how MSA is triggered and these observations in prodromal MSA led us to hypothesize that synucleinopathy could be triggered by infection of the genitourinary tract causing ɑ-synuclein (ɑSyn) to aggregate in peripheral nerves innervating these organs. As a first proof that peripheral infections could act as a trigger in MSA, this study focused on lower urinary tract infections (UTIs), given the relevance and high frequency of UTIs in prodromal MSA, although other types of infection might also be important triggers of MSA. We performed an epidemiological nested-case control study in the Danish population showing that UTIs are associated with future diagnosis of MSA several years after infection and that it impacts risk in both men and women. Bacterial infection of the urinary bladder triggers synucleinopathy in mice and we propose a novel role of ɑSyn in the innate immune system response to bacteria. Urinary tract infection with uropathogenic <i>E.</i> <i>coli</i> results in the de novo aggregation of ɑSyn during neutrophil infiltration. During the infection, ɑSyn is released extracellularly from neutrophils as part of their extracellular traps. Injection of MSA aggregates into the urinary bladder leads to motor deficits and propagation of ɑSyn pathology to the central nervous system in mice overexpressing oligodendroglial ɑSyn. Repeated UTIs lead to progressive development of synucleinopathy with oligodendroglial involvement in vivo. Our results link bacterial infections with synucleinopathy and show that a host response to environmental triggers can result in ɑSyn pathology that bears semblance to MSA.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"145 5","pages":"541 - 559"},"PeriodicalIF":12.7,"publicationDate":"2023-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-023-02562-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9399731","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}