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Brain transcriptome analysis of a CLN2 mouse model as a function of disease progression
Miriam S Domowicz1, Wen-Ching Chan2, Patricia Claudio-Vázquez3
1Department of Pediatrics, Biological Sciences Division, The University of Chicago Medical Center, 5841 S. Maryland Avenue, MC 5058, Chicago, IL, 60637, USA. mdxx@uchicago.edu.
This study reveals that neuroinflammation in Batten disease begins after two months, with rapid microglial and astrocyte activation in the cerebellum. These findings enhance understanding of classical late infantile NCL progression for potential therapeutic development.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Neuronal ceroid lipofuscinoses (NCLs), or Batten disease, are fatal inherited neurodegenerative disorders.
- Caused by mutations in 13 genes, NCLs feature lysosomal storage and neurodegeneration, with unclear gene-function relationships.
- This study uses a mouse model of classical late infantile NCL (cLINCL) with a disrupted tripeptidyl peptidase 1 (Tpp1) gene.
Purpose of the Study:
- To identify genes and pathways contributing to neurodegeneration in TPP1-deficient mice.
- To analyze transcriptional differences in the brain during disease progression.
- To understand the temporal and regional onset of neuroinflammation.
Main Methods:
- Global RNA-sequencing of forebrain/midbrain and cerebellum in control and TPP1-deficient mice at 1, 2, 3, and 4 months of age.
- Analysis of transcriptional changes to identify disease-associated genes and pathways.
- Assessment of inflammatory responses, including glial cell activation and gene expression markers.
Main Results:
- Progressive neuroinflammation involving microglia, astrocytes, and endothelial cells was observed.
- Specific astrocytic and microglial genes (e.g., Gfap, Ctss) were identified as markers of disease progression.
- Neuroinflammation initiated primarily after 2 months, with faster microglial and astrocyte activation in the cerebellum.
Conclusions:
- Neuroinflammation in cLINCL begins after 2 months, with cerebellum being more severely affected.
- Early choroid plexus gene expression suggests a role in disease pathology.
- Findings improve understanding of cLINCL pathogenesis, aiding future therapeutic strategies.
