Brain gene expression profiles of Cln1 and Cln5 deficient mice unravels common molecular pathways underlying neuronal degeneration in NCL diseases

The neuronal ceroid lipofuscinoses (NCL) are a group of childhood inherited neurodegenerative disorders characterized by blindness, early dementia and pronounced cortical atrophy. The similar pathological and clinical profiles of different forms of NCL suggest that common disease mechanisms may be involved. Here, we have performed quantitative gene expression profiling of cortex from targeted knock out mice produced for Cln1 and Cln5 to explore NCL-associated molecular pathways. Combined microarray datasets from both mouse models exposed a common affected pathway: genes regulating cytoskeletal dynamics and neuronal growth cone stabilization display similar aberrations. We analyzed locus specific gene expression and showed regional clustering of Cln1 and three major genes of this pathway, further supporting a close functional relationship between the corresponding gene products, Cap1, Ptprf and Ptp4a2. The evidence from the gene expression data was substantiated by immunohistochemical staining data of Cln1-/- and Cln5-/- cortical neurons. These primary neurons displayed abnormalities in beta-tubulin and actin as well as abnormal intracellular distribution of growth cone associated proteins GAP-43, synapsin and Rab3. Our data provide the first evidence for a common molecular pathogenesis behind neuronal degeneration in CLN1 and CLN5. Since CLN1 and CLN5 code for proteins with distinct functional roles these data may have implications for other forms of NCL.

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von Schantz C, Saharinen J, Kopra O, Cooper JD, Gentile M, Hovatta I, Peltonen L, Jalanko A