Brain transcriptome analysis of a CLN2 mouse model as a function of disease progression

Abstract Background Neuronal ceroid lipofuscinoses, (NCLs or Batten disease) are a group of inherited, early onset, fatal neurodegenerative diseases associated with mutations in 13 genes. All forms of the disease are characterized by lysosomal accumulation of fluorescent storage material, as well as...

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Autores principales:	Miriam S. Domowicz, Wen-Ching Chan, Patricia Claudio-Vázquez, Tatiana Gonzalez, Nancy B. Schwartz
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Neuronal ceroid lipofuscinoses Transcriptome Lysosomal tripeptidyl peptidase 1 Pediatric neurodegeneration Neuroinflammation Choroid plexus Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/ee4c858595e646ac95008449adb9a7e0
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spelling	oai:doaj.org-article:ee4c858595e646ac95008449adb9a7e02021-11-14T12:38:15ZBrain transcriptome analysis of a CLN2 mouse model as a function of disease progression10.1186/s12974-021-02302-z1742-2094https://doaj.org/article/ee4c858595e646ac95008449adb9a7e02021-11-01T00:00:00Zhttps://doi.org/10.1186/s12974-021-02302-zhttps://doaj.org/toc/1742-2094Abstract Background Neuronal ceroid lipofuscinoses, (NCLs or Batten disease) are a group of inherited, early onset, fatal neurodegenerative diseases associated with mutations in 13 genes. All forms of the disease are characterized by lysosomal accumulation of fluorescent storage material, as well as profound neurodegeneration, but the relationship of the various genes’ function to a single biological process is not obvious. In this study, we used a well-characterized mouse model of classical late infantile NCL (cLINCL) in which the tripeptidyl peptidase 1 (Tpp1) gene is disrupted by gene targeting, resulting in loss of detectable TPP1 activity and leading to progressive neurological phenotypes including ataxia, increased motor deficiency, and early death. Methods In order to identify genes and pathways that may contribute to progression of the neurodegenerative process, we analyzed forebrain/midbrain and cerebellar transcriptional differences at 1, 2, 3 and 4 months of age in control and TPP1-deficient mice by global RNA-sequencing. Results Progressive neurodegenerative inflammatory responses involving microglia, astrocytes and endothelial cells were observed, accompanied by activation of leukocyte extravasation signals and upregulation of nitric oxide production and reactive oxygen species. Several astrocytic (i.e., Gfap, C4b, Osmr, Serpina3n) and microglial (i.e., Ctss, Itgb2, Itgax, Lyz2) genes were identified as strong markers for assessing disease progression as they showed increased levels of expression in vivo over time. Furthermore, transient increased expression of choroid plexus genes was observed at 2 months in the lateral and fourth ventricle, highlighting an early role for the choroid plexus and cerebrospinal fluid in the disease pathology. Based on these gene expression changes, we concluded that neuroinflammation starts, for the most part, after 2 months in the Tpp1 −/− brain and that activation of microglia and astrocytes occur more rapidly in cerebellum than in the rest of the brain; confirming increased severity of inflammation in this region. Conclusions These findings have led to a better understanding of cLINCL pathological onset and progression, which may aid in development of future therapeutic treatments for this disease.Miriam S. DomowiczWen-Ching ChanPatricia Claudio-VázquezTatiana GonzalezNancy B. SchwartzBMCarticleNeuronal ceroid lipofuscinosesTranscriptomeLysosomal tripeptidyl peptidase 1Pediatric neurodegenerationNeuroinflammationChoroid plexusNeurology. Diseases of the nervous systemRC346-429ENJournal of Neuroinflammation, Vol 18, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neuronal ceroid lipofuscinoses Transcriptome Lysosomal tripeptidyl peptidase 1 Pediatric neurodegeneration Neuroinflammation Choroid plexus Neurology. Diseases of the nervous system RC346-429
spellingShingle	Neuronal ceroid lipofuscinoses Transcriptome Lysosomal tripeptidyl peptidase 1 Pediatric neurodegeneration Neuroinflammation Choroid plexus Neurology. Diseases of the nervous system RC346-429 Miriam S. Domowicz Wen-Ching Chan Patricia Claudio-Vázquez Tatiana Gonzalez Nancy B. Schwartz Brain transcriptome analysis of a CLN2 mouse model as a function of disease progression
description	Abstract Background Neuronal ceroid lipofuscinoses, (NCLs or Batten disease) are a group of inherited, early onset, fatal neurodegenerative diseases associated with mutations in 13 genes. All forms of the disease are characterized by lysosomal accumulation of fluorescent storage material, as well as profound neurodegeneration, but the relationship of the various genes’ function to a single biological process is not obvious. In this study, we used a well-characterized mouse model of classical late infantile NCL (cLINCL) in which the tripeptidyl peptidase 1 (Tpp1) gene is disrupted by gene targeting, resulting in loss of detectable TPP1 activity and leading to progressive neurological phenotypes including ataxia, increased motor deficiency, and early death. Methods In order to identify genes and pathways that may contribute to progression of the neurodegenerative process, we analyzed forebrain/midbrain and cerebellar transcriptional differences at 1, 2, 3 and 4 months of age in control and TPP1-deficient mice by global RNA-sequencing. Results Progressive neurodegenerative inflammatory responses involving microglia, astrocytes and endothelial cells were observed, accompanied by activation of leukocyte extravasation signals and upregulation of nitric oxide production and reactive oxygen species. Several astrocytic (i.e., Gfap, C4b, Osmr, Serpina3n) and microglial (i.e., Ctss, Itgb2, Itgax, Lyz2) genes were identified as strong markers for assessing disease progression as they showed increased levels of expression in vivo over time. Furthermore, transient increased expression of choroid plexus genes was observed at 2 months in the lateral and fourth ventricle, highlighting an early role for the choroid plexus and cerebrospinal fluid in the disease pathology. Based on these gene expression changes, we concluded that neuroinflammation starts, for the most part, after 2 months in the Tpp1 −/− brain and that activation of microglia and astrocytes occur more rapidly in cerebellum than in the rest of the brain; confirming increased severity of inflammation in this region. Conclusions These findings have led to a better understanding of cLINCL pathological onset and progression, which may aid in development of future therapeutic treatments for this disease.
format	article
author	Miriam S. Domowicz Wen-Ching Chan Patricia Claudio-Vázquez Tatiana Gonzalez Nancy B. Schwartz
author_facet	Miriam S. Domowicz Wen-Ching Chan Patricia Claudio-Vázquez Tatiana Gonzalez Nancy B. Schwartz
author_sort	Miriam S. Domowicz
title	Brain transcriptome analysis of a CLN2 mouse model as a function of disease progression
title_short	Brain transcriptome analysis of a CLN2 mouse model as a function of disease progression
title_full	Brain transcriptome analysis of a CLN2 mouse model as a function of disease progression
title_fullStr	Brain transcriptome analysis of a CLN2 mouse model as a function of disease progression
title_full_unstemmed	Brain transcriptome analysis of a CLN2 mouse model as a function of disease progression
title_sort	brain transcriptome analysis of a cln2 mouse model as a function of disease progression
publisher	BMC
publishDate	2021
url	https://doaj.org/article/ee4c858595e646ac95008449adb9a7e0
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_version_	1718429142544809984

Brain transcriptome analysis of a CLN2 mouse model as a function of disease progression

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