A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in an AAV-C9ORF72 (G4C2)66 mouse model
Abstract The G4C2 hexanucleotide repeat expansion in C9ORF72 is the major genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Despite considerable efforts, the development of mouse models of C9-ALS/FTD useful for therapeutic development has prove...
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BMC
2024-12-01
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| Series: | Acta Neuropathologica Communications |
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| Online Access: | https://doi.org/10.1186/s40478-024-01911-y |
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| author | Emily G. Thompson Olivia Spead Suleyman C. Akerman Carrie Curcio Benjamin L. Zaepfel Erica R. Kent Thomas Philips Balaji G. Vijayakumar Anna Zacco Weibo Zhou Guhan Nagappan Jeffrey D. Rothstein |
| author_facet | Emily G. Thompson Olivia Spead Suleyman C. Akerman Carrie Curcio Benjamin L. Zaepfel Erica R. Kent Thomas Philips Balaji G. Vijayakumar Anna Zacco Weibo Zhou Guhan Nagappan Jeffrey D. Rothstein |
| author_sort | Emily G. Thompson |
| collection | DOAJ |
| description | Abstract The G4C2 hexanucleotide repeat expansion in C9ORF72 is the major genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Despite considerable efforts, the development of mouse models of C9-ALS/FTD useful for therapeutic development has proven challenging due to the intricate interplay of genetic and molecular factors underlying this neurodegenerative disorder, in addition to species differences. This study presents a robust investigation of the cellular pathophysiology and behavioral outcomes in a previously described AAV mouse model of C9-ALS expressing 66 G4C2 hexanucleotide repeats. The model displays key molecular ALS pathological markers including RNA foci, dipeptide repeat (DPR) protein aggregation, p62 positive stress granule formation as well as mild gliosis. However, the AAV-(G4C2)66 mouse model in this study has marginal neurodegeneration with negligible neuronal loss, or clinical deficits. Human C9orf72 is typically associated with altered TAR DNA-binding protein (TDP-43) function, yet studies of this rodent model revealed no significant evidence of TDP-43 dysfunction. While our findings indicate and support that this is a highly valuable robust and pharmacologically tractable model for investigating the molecular mechanisms and cellular consequences of (G4C2) repeat driven DPR pathology, it is not suitable for investigating the development of disease- associated TDP-43 dysfunction or clinical impairment. Our findings underscore the complexity of ALS pathogenesis involving genetic mutations and protein dysregulation and highlight the need for more comprehensive model systems that reliably replicate the multifaceted cellular and behavioral aspects of C9-ALS. |
| format | Article |
| id | doaj-art-ef9cce1204c84ddebbb73bee8dcedf16 |
| institution | DOAJ |
| issn | 2051-5960 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj-art-ef9cce1204c84ddebbb73bee8dcedf162025-08-20T02:39:35ZengBMCActa Neuropathologica Communications2051-59602024-12-0112112410.1186/s40478-024-01911-yA robust evaluation of TDP-43, poly GP, cellular pathology and behavior in an AAV-C9ORF72 (G4C2)66 mouse modelEmily G. Thompson0Olivia Spead1Suleyman C. Akerman2Carrie Curcio3Benjamin L. Zaepfel4Erica R. Kent5Thomas Philips6Balaji G. Vijayakumar7Anna Zacco8Weibo Zhou9Guhan Nagappan10Jeffrey D. Rothstein11Brain Science Institute, Johns Hopkins University School of Medicine, Johns Hopkins UniversityBrain Science Institute, Johns Hopkins University School of Medicine, Johns Hopkins UniversityBrain Science Institute, Johns Hopkins University School of Medicine, Johns Hopkins UniversityGlaxo Smith Kline Research and DevelopmentBrain Science Institute, Johns Hopkins University School of Medicine, Johns Hopkins UniversityBrain Science Institute, Johns Hopkins University School of Medicine, Johns Hopkins UniversityBrain Science Institute, Johns Hopkins University School of Medicine, Johns Hopkins UniversityBrain Science Institute, Johns Hopkins University School of Medicine, Johns Hopkins UniversityGlaxo Smith Kline Research and DevelopmentBrain Science Institute, Johns Hopkins University School of Medicine, Johns Hopkins UniversityGlaxo Smith Kline Research and DevelopmentBrain Science Institute, Johns Hopkins University School of Medicine, Johns Hopkins UniversityAbstract The G4C2 hexanucleotide repeat expansion in C9ORF72 is the major genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Despite considerable efforts, the development of mouse models of C9-ALS/FTD useful for therapeutic development has proven challenging due to the intricate interplay of genetic and molecular factors underlying this neurodegenerative disorder, in addition to species differences. This study presents a robust investigation of the cellular pathophysiology and behavioral outcomes in a previously described AAV mouse model of C9-ALS expressing 66 G4C2 hexanucleotide repeats. The model displays key molecular ALS pathological markers including RNA foci, dipeptide repeat (DPR) protein aggregation, p62 positive stress granule formation as well as mild gliosis. However, the AAV-(G4C2)66 mouse model in this study has marginal neurodegeneration with negligible neuronal loss, or clinical deficits. Human C9orf72 is typically associated with altered TAR DNA-binding protein (TDP-43) function, yet studies of this rodent model revealed no significant evidence of TDP-43 dysfunction. While our findings indicate and support that this is a highly valuable robust and pharmacologically tractable model for investigating the molecular mechanisms and cellular consequences of (G4C2) repeat driven DPR pathology, it is not suitable for investigating the development of disease- associated TDP-43 dysfunction or clinical impairment. Our findings underscore the complexity of ALS pathogenesis involving genetic mutations and protein dysregulation and highlight the need for more comprehensive model systems that reliably replicate the multifaceted cellular and behavioral aspects of C9-ALS.https://doi.org/10.1186/s40478-024-01911-yAmyotrophic lateral sclerosisC9orf72 repeat expansionDipeptide repeatsP62NfLGFAP |
| spellingShingle | Emily G. Thompson Olivia Spead Suleyman C. Akerman Carrie Curcio Benjamin L. Zaepfel Erica R. Kent Thomas Philips Balaji G. Vijayakumar Anna Zacco Weibo Zhou Guhan Nagappan Jeffrey D. Rothstein A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in an AAV-C9ORF72 (G4C2)66 mouse model Acta Neuropathologica Communications Amyotrophic lateral sclerosis C9orf72 repeat expansion Dipeptide repeats P62 NfL GFAP |
| title | A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in an AAV-C9ORF72 (G4C2)66 mouse model |
| title_full | A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in an AAV-C9ORF72 (G4C2)66 mouse model |
| title_fullStr | A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in an AAV-C9ORF72 (G4C2)66 mouse model |
| title_full_unstemmed | A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in an AAV-C9ORF72 (G4C2)66 mouse model |
| title_short | A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in an AAV-C9ORF72 (G4C2)66 mouse model |
| title_sort | robust evaluation of tdp 43 poly gp cellular pathology and behavior in an aav c9orf72 g4c2 66 mouse model |
| topic | Amyotrophic lateral sclerosis C9orf72 repeat expansion Dipeptide repeats P62 NfL GFAP |
| url | https://doi.org/10.1186/s40478-024-01911-y |
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