Gene expression profiling in a mouse model of infantile neuronal ceroid lipofuscinosis reveals upregulation of immediate early genes and mediators of the inflammatory response

Background: The infantile form of neuronal ceroid lipofuscinosis (also known as infantile Batten disease) is caused by hereditary deficiency of a lysosomal enzyme, palmitoyl-protein thioesterase-I (PPTI), and is characterized by severe cortical degeneration with blindness and cognitive and motor dysfunction. The PPTI-deficient knockout mouse recapitulates the key features of the disorder, including seizures and death by 7-9 months of age. In the current study, we compared gene expression profiles of whole brain from PPTI knockout and normal mice at 3, 5 and 8 months of age to identify temporal changes in molecular pathways implicated in disease pathogenesis. Results: A total of 267 genes were significantly (approximately 2-fold) up- or downregulated over the course of the disease. Immediate early genes (Arc, Cyr6I, c-fos, jun-b, btg2, NR4AI) were among the first genes upregulated during the presymptomatic period whereas immune response genes dominated at later time points. Chemokine ligands and protease inhibitors were among the most transcriptionally responsive genes. Neuronal survival factors (IGF-I and CNTF) and a negative regulator of neuronal apoptosis (DAP kinase-I) were upregulated late in the course of the disease. Few genes were downregulated; these included the alpha 2 subunit of the GABA-A receptor, a component of cortical and hippocampal neurons, and Hes5, a transcription factor important in neuronal differentiation. Conclusion: A molecular description of gene expression changes occurring in the brain throughout the course of neuronal ceroid lipofuscinosis suggests distinct phases of disease progression, provides clues to potential markers of disease activity, and points to new targets for therapy.