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Global Brain Transcriptome Analysis of a Tpp1 Neuronal Ceroid Lipofuscinoses Mouse Model.
Domowicz, Miriam S; Chan, Wen-Ching; Claudio-Vázquez, Patricia; Henry, Judith G; Ware, Christopher B; Andrade, Jorge; Dawson, Glyn; Schwartz, Nancy B.
Afiliación
  • Domowicz MS; 1 Department of Pediatrics, Biological Sciences Division, The University of Chicago, IL, USA.
  • Chan WC; 2 Center for Research Informatics, Biological Sciences Division, The University of Chicago, IL, USA.
  • Claudio-Vázquez P; 1 Department of Pediatrics, Biological Sciences Division, The University of Chicago, IL, USA.
  • Henry JG; 1 Department of Pediatrics, Biological Sciences Division, The University of Chicago, IL, USA.
  • Ware CB; 1 Department of Pediatrics, Biological Sciences Division, The University of Chicago, IL, USA.
  • Andrade J; 2 Center for Research Informatics, Biological Sciences Division, The University of Chicago, IL, USA.
  • Dawson G; 1 Department of Pediatrics, Biological Sciences Division, The University of Chicago, IL, USA.
  • Schwartz NB; 1 Department of Pediatrics, Biological Sciences Division, The University of Chicago, IL, USA.
ASN Neuro ; 11: 1759091419843393, 2019.
Article en En | MEDLINE | ID: mdl-31003587
In humans, homozygous mutations in the TPP1 gene results in loss of tripeptidyl peptidase 1 (TPP1) enzymatic activity, leading to late infantile neuronal ceroid lipofuscinoses disease. Using a mouse model that targets the Tpp1 gene and recapitulates the pathology and clinical features of the human disease, we analyzed end-stage (4 months) transcriptional changes associated with lack of TPP1 activity. Using RNA sequencing technology, Tpp1 expression changes in the forebrain/midbrain and cerebellum of 4-month-old homozygotes were compared with strain-related controls. Transcriptional changes were found in 510 and 1,550 gene transcripts in forebrain/midbrain and cerebellum, respectively, from Tpp1-deficient brain tissues when compared with age-matched controls. Analysis of the differentially expressed genes using the Ingenuity™ pathway software, revealed increased neuroinflammation activity in microglia and astrocytes that could lead to neuronal dysfunction, particularly in the cerebellum. We also observed upregulation in the production of nitric oxide and reactive oxygen species; activation of leukocyte extravasation signals and complement pathways; and downregulation of major transcription factors involved in control of circadian rhythm. Several of these expression changes were confirmed by independent quantitative polymerase chain reaction and histological analysis by mRNA in situ hybridization, which allowed for an in-depth anatomical analysis of the pathology and provided independent confirmation of at least two of the major networks affected in this model. The identification of differentially expressed genes has revealed new lines of investigation for this complex disorder that may lead to novel therapeutic targets.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Regulación de la Expresión Génica / Dipeptidil-Peptidasas y Tripeptidil-Peptidasas / Serina Proteasas / Transcriptoma / Aminopeptidasas / Lipofuscinosis Ceroideas Neuronales Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: ASN Neuro Asunto de la revista: NEUROLOGIA / QUIMICA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Regulación de la Expresión Génica / Dipeptidil-Peptidasas y Tripeptidil-Peptidasas / Serina Proteasas / Transcriptoma / Aminopeptidasas / Lipofuscinosis Ceroideas Neuronales Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: ASN Neuro Asunto de la revista: NEUROLOGIA / QUIMICA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos