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

A total of 267 genes were significantly (approximately 2-fold) up- or downregulated over the course of the disease. Immediate early genes (Arc, Cyr61, c-fos, jun-b, btg2, NR4A1) 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-1 and CNTF) and a negative regulator of neuronal apoptosis (DAP kinase-1) were upregulated late in the course of the disease. Few genes were downregulated; these included the α2 subunit of the GABA-A receptor, a component of cortical and hippocampal neurons, and Hes5, a transcription factor important in neuronal differentiation.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.An unusual group of lysosomal storage disorders, the neuronal ceroid lipofuscinoses, are characterized by retinal and cortical neurodegeneration with scant autofluorescent storage material that accumulates in the brain and peripheral tissues (reviewed in [1]). Distinct subsets of NCL are recognized based on characteristic appearance by electron microscopy that include granular osmiophilic deposits and/or various membrane profiles (curvilinear, fingerprint, and rectilinear) [2]. Autosomal recessive mutations in at least seven different genes are responsible for these disorders [3], and while the function of only a few is known, each appears to participate in some aspect of endo/lysosomal function [4]. The CLN1 (ceroid lipofuscinosis, neuronal-1) gene encodes a soluble lysosomal palmitoyl-protein thioesterase (PPT1) that functions to remove fatty acids (usually palmitate) from modified cysteine residues in proteins [5,6]. A growing number of s