modeling-posthemorrhagic-hydrocephalus-of-prematurity-in-rats

Modeling Posthemorrhagic Hydrocephalus of Prematurity in Rats

Posthemorrhagic hydrocephalus of prematurity (PHHP) is a serious sequela of severe intraventricular hemorrhage (IVH) in very preterm infants less than 32 ...

Johns Hopkins University School of Medicine

Johns Hopkins Children's Center

The GC hexanucleotide repeat expansion in  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 GC hexanucleotide repeats. Despite displaying key molecular ALS pathological markers including RNA foci, dipeptide repeat (DPR) protein aggregation, p62 positive stress granule formation as well as mild gliosis, the AAV-(GC) mouse model in this study exhibits negligible neuronal loss, no motor deficits, and functionally unimpaired TAR DNA-binding protein-43 (TDP-43). While our findings indicate and support that this is a robust and pharmacologically tractable model for investigating the molecular mechanisms and cellular consequences of (GC) repeat driven DPR pathology, it is not suitable for investigating the development of disease associated neurodegeneration, TDP-43 dysfunction, gliosis, and motor performance. 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.

A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in a AAV-C9ORF72 (GC) mouse model.

The GC hexanucleotide repeat expansion in  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 GC 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-(GC) 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 (GC) 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.

A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in a AAV- C9ORF72 (G 4 C 2) 66 mouse model.

The GC 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 GC 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-(GC) 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 (GC) 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.

Balaji Vijayakumar

Division of Neonatal-Perinatal Medicine

Johns Hopkins University School of Medicine

Modeling Posthemorrhagic Hydrocephalus of Prematurity in Rats

Balaji Vijayakumar

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Division of Neonatal-Perinatal Medicine

Johns Hopkins University School of Medicine

Modeling Posthemorrhagic Hydrocephalus of Prematurity in Rats

Division of Neonatal-Perinatal Medicine