Acta Neuropathologica最新文献

{"title":"Current insights and assumptions on α-synuclein in Lewy body disease","authors":"Rehana K. Leak,&nbsp;Rachel N. Clark,&nbsp;Muslim Abbas,&nbsp;Fei Xu,&nbsp;Jeffrey L. Brodsky,&nbsp;Jun Chen,&nbsp;Xiaoming Hu,&nbsp;Kelvin C. Luk","doi":"10.1007/s00401-024-02781-3","DOIUrl":"10.1007/s00401-024-02781-3","url":null,"abstract":"<div><p>Lewy body disorders are heterogeneous neurological conditions defined by intracellular inclusions composed of misshapen α-synuclein protein aggregates. Although α-synuclein aggregates are only one component of inclusions and not strictly coupled to neurodegeneration, evidence suggests they seed the propagation of Lewy pathology within and across cells. Genetic mutations, genomic multiplications, and sequence polymorphisms of the gene encoding α-synuclein are also causally linked to Lewy body disease. In nonfamilial cases of Lewy body disease, the disease trigger remains unidentified but may range from industrial/agricultural toxicants and natural sources of poisons to microbial pathogens. Perhaps due to these peripheral exposures, Lewy inclusions appear at early disease stages in brain regions connected with cranial nerves I and X, which interface with inhaled and ingested environmental elements in the nasal or gastrointestinal cavities. Irrespective of its identity, a stealthy disease trigger most likely shifts soluble α-synuclein (directly or indirectly) into insoluble, cross-β-sheet aggregates. Indeed, β-sheet-rich self-replicating α-synuclein multimers reside in patient plasma, cerebrospinal fluid, and other tissues, and can be subjected to α-synuclein seed amplification assays. Thus, clinicians should be able to capitalize on α-synuclein seed amplification assays to stratify patients into potential responders <i>versus</i> non-responders in future clinical trials of α-synuclein targeted therapies. Here, we briefly review the current understanding of α-synuclein in Lewy body disease and speculate on pathophysiological processes underlying the potential transmission of α-synucleinopathy across the neuraxis.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11324801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974781","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":"ASXL1 inactivation and reduced H3K27me3 across central nervous system tumors","authors":"Kevin Y. Zhang,&nbsp;Megan Parker,&nbsp;Carly Weber-Levine,&nbsp;Anita Kalluri,&nbsp;Ignacio Gonzalez-Gomez,&nbsp;Eric Raabe,&nbsp;Jonathan C. Dudley,&nbsp;Christopher Gocke,&nbsp;Ming-Tseh Lin,&nbsp;Ying Zou,&nbsp;Mohamed Sherief,&nbsp;David O. Kamson,&nbsp;Matthias Holdhoff,&nbsp;Debraj Mukherjee,&nbsp;Victoria Croog,&nbsp;Karisa C. Schreck,&nbsp;Jordina Rincon-Torroella,&nbsp;Chetan Bettegowda,&nbsp;Charles G. Eberhart,&nbsp;Tejus Bale,&nbsp;Calixto-Hope G. Lucas","doi":"10.1007/s00401-024-02785-z","DOIUrl":"10.1007/s00401-024-02785-z","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11324662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974780","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":"Loss over 5% of chromosome 1p is a clinically relevant and applicable cut-off for increased risk of recurrence in meningioma","authors":"Sybren L. N. Maas,&nbsp;Thomas Hielscher,&nbsp;Philipp Sievers,&nbsp;Volker Hovestadt,&nbsp;Abigail K. Suwala,&nbsp;Till Acker,&nbsp;Michael Weller,&nbsp;Matthias Preusser,&nbsp;Christel Herold-Mende,&nbsp;Wolfgang Wick,&nbsp;Andreas von Deimling,&nbsp;Natalie Berghaus,&nbsp;Felix Sahm","doi":"10.1007/s00401-024-02777-z","DOIUrl":"10.1007/s00401-024-02777-z","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11310275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141900585","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":"Analysis of microisolated frontal cortex excitatory layer III and V pyramidal neurons reveals a neurodegenerative phenotype in individuals with Down syndrome","authors":"Melissa J. Alldred,&nbsp;Harshitha Pidikiti,&nbsp;Kyrillos W. Ibrahim,&nbsp;Sang Han Lee,&nbsp;Adriana Heguy,&nbsp;Gabriel E. Hoffman,&nbsp;Panos Roussos,&nbsp;Thomas Wisniewski,&nbsp;Jerzy Wegiel,&nbsp;Grace E. Stutzmann,&nbsp;Elliott J. Mufson,&nbsp;Stephen D. Ginsberg","doi":"10.1007/s00401-024-02768-0","DOIUrl":"10.1007/s00401-024-02768-0","url":null,"abstract":"<div><p>We elucidated the molecular fingerprint of vulnerable excitatory neurons within select cortical lamina of individuals with Down syndrome (DS) for mechanistic understanding and therapeutic potential that also informs Alzheimer’s disease (AD) pathophysiology. Frontal cortex (BA9) layer III (L3) and layer V (L5) pyramidal neurons were microisolated from postmortem human DS and age- and sex-matched controls (CTR) to interrogate differentially expressed genes (DEGs) and key biological pathways relevant to neurodegenerative programs. We identified &gt; 2300 DEGs exhibiting convergent dysregulation of gene expression in both L3 and L5 pyramidal neurons in individuals with DS versus CTR subjects. DEGs included over 100 triplicated human chromosome 21 genes in L3 and L5 neurons, demonstrating a trisomic neuronal karyotype in both laminae. In addition, thousands of other DEGs were identified, indicating gene dysregulation is not limited to trisomic genes in the aged DS brain, which we postulate is relevant to AD pathobiology. Convergent L3 and L5 DEGs highlighted pertinent biological pathways and identified key pathway-associated targets likely underlying corticocortical neurodegeneration and related cognitive decline in individuals with DS. Select key DEGs were interrogated as potential hub genes driving dysregulation, namely the triplicated DEGs amyloid precursor protein (APP) and superoxide dismutase 1 (SOD1), along with key signaling DEGs including mitogen activated protein kinase 1 and 3 (MAPK1, MAPK3) and calcium calmodulin dependent protein kinase II alpha (CAMK2A), among others. Hub DEGs determined from multiple pathway analyses identified potential therapeutic candidates for amelioration of cortical neuron dysfunction and cognitive decline in DS with translational relevance to AD.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02768-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892596","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":"Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease","authors":"Nur Jury-Garfe,&nbsp;Javier Redding-Ochoa,&nbsp;Yanwen You,&nbsp;Pablo Martínez,&nbsp;Hande Karahan,&nbsp;Enrique Chimal-Juárez,&nbsp;Travis S. Johnson,&nbsp;Jie Zhang,&nbsp;Susan Resnick,&nbsp;Jungsu Kim,&nbsp;Juan C. Troncoso,&nbsp;Cristian A. Lasagna-Reeves","doi":"10.1007/s00401-024-02775-1","DOIUrl":"10.1007/s00401-024-02775-1","url":null,"abstract":"<div><p>Asymptomatic Alzheimer’s disease (AsymAD) describes the status of individuals with preserved cognition but identifiable Alzheimer’s disease (AD) brain pathology (i.e., beta-amyloid (Aβ) deposits, neuritic plaques, and neurofibrillary tangles) at autopsy. In this study, we investigated the postmortem brains of a cohort of AsymAD subjects to gain insight into the mechanisms underlying resilience to AD pathology and cognitive decline. Our results showed that AsymAD cases exhibit enrichment in core plaques, decreased filamentous plaque accumulation, and increased plaque-surrounding microglia. Less pathological tau aggregation in dystrophic neurites was found in AsymAD brains than in AD brains, and tau seeding activity was comparable to that in healthy brains. We used spatial transcriptomics to characterize the plaque niche further and revealed autophagy, endocytosis, and phagocytosis as the pathways associated with the genes upregulated in the AsymAD plaque niche. Furthermore, the levels of ARP2 and CAP1, which are actin-based motility proteins that participate in the dynamics of actin filaments to allow cell motility, were increased in the microglia surrounding amyloid plaques in AsymAD cases. Our findings suggest that the amyloid-plaque microenvironment in AsymAD cases is characterized by the presence of microglia with highly efficient actin-based cell motility mechanisms and decreased tau seeding compared with that in AD brains. These two mechanisms can potentially protect against the toxic cascade initiated by Aβ, preserving brain health, and slowing AD pathology progression.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11300572/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888139","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":"Alcohol consumers with liver pathology rarely display α-synuclein pathology","authors":"Sylwia Libard,&nbsp;Fredrik Tamsen,&nbsp;Irina Alafuzoff","doi":"10.1007/s00401-024-02772-4","DOIUrl":"10.1007/s00401-024-02772-4","url":null,"abstract":"<div><p>It has been suggested that alcohol consumption protects against Parkinson's disease (PD). Here we assessed postmortem tissue samples from the brains and livers of 100 subjects with ages at death ranging from 51 to 93. Twenty percent of these subjects were demented. We used standardized assessment strategies to assess both the brain and liver pathologies (LP). Our cohort included subjects with none, mild, moderate, and severe LP caused by alcohol consumption. We noted a significant negative correlation of categorical data between liver steatosis and α-synuclein (αS) in the brain and a significant negative correlation between the extent of liver steatosis and fibrosis and the extent of αS in the brain. There was a significant negative association between the observation of Alzheimer’s type II astrocytes and αS pathology in the brain. No association was noted between LP and hyperphosphorylated τ (HPτ). No significant correlation could be seen between the extent of LP and the extent of HPτ, amyloid β protein (Aβ) or transactive DNA binding protein 43 (TDP43) in the brain. There were significant correlations observed between the extent of HPτ, Aβ, αS, and TDP43 in the brain and between liver steatosis, inflammation, and fibrosis. Subjects with severe LP displayed a higher frequency of Alzheimer’s type II astrocytes compared to those with no, or mild, LP. The assessed protein alterations were not more prevalent or severe in subjects with Alzheimer’s type II astrocytes in the brain. In all cases, dementia was attributed to a combination of altered proteins, i.e., mixed dementia and dementia was observed in 30% of those with mild LP when compared with 13% of those with severe LP. In summary, our results are in line with the outcome obtained by the two recent meta-analyses suggesting that subjects with a history of alcohol consumption seldom develop an α-synucleinopathy.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11291549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858737","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":"The parkin V380L variant is a genetic modifier of Machado–Joseph disease with impact on mitophagy","authors":"Jonasz J. Weber,&nbsp;Leah Czisch,&nbsp;Priscila Pereira Sena,&nbsp;Florian Fath,&nbsp;Chrisovalantou Huridou,&nbsp;Natasa Schwarz,&nbsp;Rana D. Incebacak Eltemur,&nbsp;Anna Würth,&nbsp;Daniel Weishäupl,&nbsp;Miriam Döcker,&nbsp;Gunnar Blumenstock,&nbsp;Sandra Martins,&nbsp;Jorge Sequeiros,&nbsp;Guy A. Rouleau,&nbsp;Laura Bannach Jardim,&nbsp;Maria-Luiza Saraiva-Pereira,&nbsp;Marcondes C. França Jr.,&nbsp;Carlos R. Gordon,&nbsp;Roy Zaltzman,&nbsp;Mario R. Cornejo-Olivas,&nbsp;Bart P. C. van de Warrenburg,&nbsp;Alexandra Durr,&nbsp;Alexis Brice,&nbsp;Peter Bauer,&nbsp;Thomas Klockgether,&nbsp;Ludger Schöls,&nbsp;Olaf Riess,&nbsp;The EUROSCA Network,&nbsp;Thorsten Schmidt","doi":"10.1007/s00401-024-02762-6","DOIUrl":"10.1007/s00401-024-02762-6","url":null,"abstract":"<div><p>Machado–Joseph disease (MJD) is an autosomal dominant neurodegenerative spinocerebellar ataxia caused by a polyglutamine-coding CAG repeat expansion in the <i>ATXN3</i> gene. While the CAG length correlates negatively with the age at onset, it accounts for approximately 50% of its variability only. Despite larger efforts in identifying contributing genetic factors, candidate genes with a robust and plausible impact on the molecular pathogenesis of MJD are scarce. Therefore, we analysed missense single nucleotide polymorphism variants in the <i>PRKN</i> gene encoding the Parkinson's disease-associated E3 ubiquitin ligase parkin, which is a well-described interaction partner of the MJD protein ataxin-3, a deubiquitinase. By performing a correlation analysis in the to-date largest MJD cohort of more than 900 individuals, we identified the V380L variant as a relevant factor, decreasing the age at onset by 3 years in homozygous carriers. Functional analysis in an MJD cell model demonstrated that parkin V380L did not modulate soluble or aggregate levels of ataxin-3 but reduced the interaction of the two proteins. Moreover, the presence of parkin V380L interfered with the execution of mitophagy—the autophagic removal of surplus or damaged mitochondria—thereby compromising cell viability. In summary, we identified the V380L variant in parkin as a genetic modifier of MJD, with negative repercussions on its molecular pathogenesis and disease age at onset.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11294389/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858738","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":"Diffuse, IDH-wildtype gliomas in adults with minimal histological change and isolated TERT promoter mutation: not simply CNS WHO grade 4","authors":"L. P. Priesterbach-Ackley,&nbsp;F. Cordier,&nbsp;P. de Witt Hamer,&nbsp;T. J. Snijders,&nbsp;P. A. Robe,&nbsp;B. Küsters,&nbsp;W. W. J. de Leng,&nbsp;W. F. A. den Dunnen,&nbsp;D. Brandsma,&nbsp;C. Jansen,&nbsp;P. Wesseling,&nbsp;A. Muhlebner","doi":"10.1007/s00401-024-02773-3","DOIUrl":"10.1007/s00401-024-02773-3","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11286727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787035","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":"High throughput spatial immune mapping reveals an innate immune scar in post-COVID-19 brains","authors":"Marius Schwabenland,&nbsp;Dilara Hasavci,&nbsp;Sibylle Frase,&nbsp;Katharina Wolf,&nbsp;Nikolaus Deigendesch,&nbsp;Joerg M. Buescher,&nbsp;Kirsten D. Mertz,&nbsp;Benjamin Ondruschka,&nbsp;Hermann Altmeppen,&nbsp;Jakob Matschke,&nbsp;Markus Glatzel,&nbsp;Stephan Frank,&nbsp;Robert Thimme,&nbsp;Juergen Beck,&nbsp;Jonas A. Hosp,&nbsp;Thomas Blank,&nbsp;Bertram Bengsch,&nbsp;Marco Prinz","doi":"10.1007/s00401-024-02770-6","DOIUrl":"10.1007/s00401-024-02770-6","url":null,"abstract":"<div><p>The underlying pathogenesis of neurological sequelae in post-COVID-19 patients remains unclear. Here, we used multidimensional spatial immune phenotyping and machine learning methods on brains from initial COVID-19 survivors to identify the biological correlate associated with previous SARS-CoV-2 challenge. Compared to healthy controls, individuals with post-COVID-19 revealed a high percentage of TMEM119⁺P2RY12⁺CD68⁺Iba1⁺HLA-DR⁺CD11c⁺SCAMP2⁺ microglia assembled in prototypical cellular nodules. In contrast to acute SARS-CoV-2 cases, the frequency of CD8⁺ parenchymal T cells was reduced, suggesting an immune shift toward innate immune activation that may contribute to neurological alterations in post-COVID-19 patients.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11281987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141764811","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":"Neuropathologically directed profiling of PRNP somatic and germline variants in sporadic human prion disease","authors":"Gannon A. McDonough,&nbsp;Yuchen Cheng,&nbsp;Katherine S. Morillo,&nbsp;Ryan N. Doan,&nbsp;Zinan Zhou,&nbsp;Connor J. Kenny,&nbsp;Aaron Foutz,&nbsp;Chae Kim,&nbsp;Mark L. Cohen,&nbsp;Brian S. Appleby,&nbsp;Christopher A. Walsh,&nbsp;Jiri G. Safar,&nbsp;August Yue Huang,&nbsp;Michael B. Miller","doi":"10.1007/s00401-024-02774-2","DOIUrl":"10.1007/s00401-024-02774-2","url":null,"abstract":"<div><p>Creutzfeldt–Jakob Disease (CJD), the most common human prion disease, is associated with pathologic misfolding of the prion protein (PrP), encoded by the <i>PRNP</i> gene. Of human prion disease cases, &lt; 1% were transmitted by misfolded PrP, ~ 15% are inherited, and ~ 85% are sporadic (sCJD). While familial cases are inherited through germline mutations in <i>PRNP</i>, the cause of sCJD is unknown. Somatic mutations have been hypothesized as a cause of sCJD, and recent studies have revealed that somatic mutations accumulate in neurons during aging. To investigate the hypothesis that somatic mutations in <i>PRNP</i> may underlie sCJD, we performed deep DNA sequencing of <i>PRNP</i> in 205 sCJD cases and 170 age-matched non-disease controls. We included 5 cases of Heidenhain variant sporadic CJD (H-sCJD), where visual symptomatology and neuropathology implicate localized initiation of prion formation, and examined multiple regions across the brain including in the affected occipital cortex. We employed Multiple Independent Primer PCR Sequencing (MIPP-Seq) with a median depth of &gt; 5000× across the <i>PRNP</i> coding region and analyzed for variants using MosaicHunter. An allele mixing experiment showed positive detection of variants in bulk DNA at a variant allele fraction (VAF) as low as 0.2%. We observed multiple polymorphic germline variants among individuals in our cohort. However, we did not identify bona fide somatic variants in sCJD, including across multiple affected regions in H-sCJD, nor in control individuals. Beyond our stringent variant-identification pipeline, we also analyzed VAFs from raw sequencing data, and observed no evidence of prion disease enrichment for the known germline pathogenic variants P102L, D178N, and E200K. The lack of <i>PRNP</i> pathogenic somatic mutations in H-sCJD or the broader cohort of sCJD suggests that clonal somatic mutations may not play a major role in sporadic prion disease. With H-sCJD representing a localized presentation of neurodegeneration, this serves as a test of the potential role of clonal somatic mutations in genes known to cause familial neurodegeneration.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141755202","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}