Several genetic defects of the nucleotide excision repair (NER) pathway, including deficiency of the Excision Repair Cross-Complementing rodent repair deficiency, complementation group 1 (ERCC1), result in pre-mature aging, impaired growth, microcephaly and delayed development of the cerebellum. These phenotypes are recapitulated in Ercc1-knockout mice, which survive for up to 4 weeks after birth. Therefore, we analyzed cerebellar and hippocampal transcriptomes of these animals at 3 weeks of age to identify the candidate mechanisms underlying central nervous system abnormalities caused by inherited defects in NER. In the cerebellum, the most prominent change was the upregulation of genes associated with gliosis. Although Purkinje cell degeneration has been reported in some mouse strains with NER impairment, the transcripts whose downregulation is associated with Purkinje cell loss were mostly unaffected by the knockout of Ercc1. In the hippocampus, there was extensive downregulation of genes related to cholesterol biosynthesis. Reduced expression of these genes was also present in the neocortex of adult mice with reduced expression of ERCC1. These changes were accompanied by reduced mRNA expression of the transcription factor Sterol Regulatory Element Binding Transcription Factor-2 (SREBF2) which is a master regulator of cholesterol biosynthesis. The downregulation of forebrain cholesterol biosynthesis genes is a newly identified consequence of ERCC1 deficiency. Reduced cholesterol biosynthesis may contribute to the neurodevelopmental disruption that is associated with ERCC1 defects and several other NER deficiencies including Cockayne syndrome. In addition, this reduction may negatively affect the function of mature synapses.
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