Spinocerebellar ataxia(SCA)type 51 is a neurodegenerative disease caused by CAG repeat expansions in exon 1 of the THAP11 gene.These repeats are translated into a glutamine-rich protein,THAP11-polyQ,which forms protei...Spinocerebellar ataxia(SCA)type 51 is a neurodegenerative disease caused by CAG repeat expansions in exon 1 of the THAP11 gene.These repeats are translated into a glutamine-rich protein,THAP11-polyQ,which forms protein aggregates and exhibits toxicity in cell models;however,the underlying mechanism remains unclear.In this study,we generate transgenic Drosophila models expressing varying lengths of THAP11-polyQ using the UAS-GAL4 system and assess neurodegeneration through pathological and behavioral analyses.Our results demonstrate that expression of THAP11-polyQ in transgenic flies leads to progressive neuronal cell loss,locomotor deficiency,and reduced survival.RNA sequencing of patient-derived skin fibroblasts reveals significant enrichment of the PI3K–Akt–mTOR pathway,and electron microscopy of transgenic flies shows an increase in multilamellar bodies,suggesting involvement of autophagy in SCA51.Consequently,we treat the fly model with rapamycin,an mTOR inhibitor known to enhance autophagy.This treatment reduces toxic THAP11-polyQ protein aggregates,significantly alleviates neuronal degeneration,and improves locomotor function,consistent with the rescue effects observed upon overexpression of Atg8a.Overall,these findings suggest that the Drosophila model,which recapitulates the neurodegenerative features of SCA51,can be used to investigate pathogenic mechanisms and that rapamycin holds promising potential as a therapeutic approach for this disease.展开更多
Schwannoma is a well-described,benign nerve sheath tumor of the soft tissue,but is rare in the gastrointestinal tract.Gastrointestinal schwannomas are often incidentally discovered as small polypoid intraluminal lesio...Schwannoma is a well-described,benign nerve sheath tumor of the soft tissue,but is rare in the gastrointestinal tract.Gastrointestinal schwannomas are often incidentally discovered as small polypoid intraluminal lesions.In this report,we describe the clinicopathologic and immunohistochemical features of a distinctive neural mucosal polyp composed of a diffuse cellular proliferation of uniform bland spindled cells in the lamina propria that entraps the colonic crypts.Immunohistochemical analysis revealed strong and diffuse positivity for the S-100 protein.To avoid confusion of these solitary colorectal polyps containing pure spindled Schwann cell proliferation in the lamina propria with neural lesions that have significant association with inherited syndromes,it is better to use the designation "mucosal Schwann hamartoma".展开更多
基金financially supported by the National Natural Science Foundation of China(82402177,82171846,82422025,82471430)Clinical Medicine Plus X-Young Scholars Project of Peking University(PKU2025PKULCXQ026)+1 种基金National High Level Hospital Clinical Research Funding(Interdepartmental Research Project of Peking University First Hospital,2023IR51,High Quality Clinical Research Project of Peking University First Hospital,2022CR69)Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases(BZ0317).
文摘Spinocerebellar ataxia(SCA)type 51 is a neurodegenerative disease caused by CAG repeat expansions in exon 1 of the THAP11 gene.These repeats are translated into a glutamine-rich protein,THAP11-polyQ,which forms protein aggregates and exhibits toxicity in cell models;however,the underlying mechanism remains unclear.In this study,we generate transgenic Drosophila models expressing varying lengths of THAP11-polyQ using the UAS-GAL4 system and assess neurodegeneration through pathological and behavioral analyses.Our results demonstrate that expression of THAP11-polyQ in transgenic flies leads to progressive neuronal cell loss,locomotor deficiency,and reduced survival.RNA sequencing of patient-derived skin fibroblasts reveals significant enrichment of the PI3K–Akt–mTOR pathway,and electron microscopy of transgenic flies shows an increase in multilamellar bodies,suggesting involvement of autophagy in SCA51.Consequently,we treat the fly model with rapamycin,an mTOR inhibitor known to enhance autophagy.This treatment reduces toxic THAP11-polyQ protein aggregates,significantly alleviates neuronal degeneration,and improves locomotor function,consistent with the rescue effects observed upon overexpression of Atg8a.Overall,these findings suggest that the Drosophila model,which recapitulates the neurodegenerative features of SCA51,can be used to investigate pathogenic mechanisms and that rapamycin holds promising potential as a therapeutic approach for this disease.
文摘Schwannoma is a well-described,benign nerve sheath tumor of the soft tissue,but is rare in the gastrointestinal tract.Gastrointestinal schwannomas are often incidentally discovered as small polypoid intraluminal lesions.In this report,we describe the clinicopathologic and immunohistochemical features of a distinctive neural mucosal polyp composed of a diffuse cellular proliferation of uniform bland spindled cells in the lamina propria that entraps the colonic crypts.Immunohistochemical analysis revealed strong and diffuse positivity for the S-100 protein.To avoid confusion of these solitary colorectal polyps containing pure spindled Schwann cell proliferation in the lamina propria with neural lesions that have significant association with inherited syndromes,it is better to use the designation "mucosal Schwann hamartoma".
