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Open Access Highly Accessed Research article

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

Carina von Schantz1, Juha Saharinen12, Outi Kopra134, Jonathan D Cooper5, Massimiliano Gentile2, Iiris Hovatta16, Leena Peltonen178 and Anu Jalanko1*

Author Affiliations

1 National Public Health Institute and FIMM, Institute for Molecular Medicine, Helsinki, Finland

2 Genome Informatics Unit, University of Helsinki, Finland

3 Folkhälsan Institute of Genetics, Helsinki, Finland

4 Neuroscience Center, University of Helsinki, Finland

5 Institute of Psychiatry, King's College, London

6 University of Helsinki, Department of Medical Genetics and Research Program of Molecular Neurology, Biomedicum Helsinki, Finland

7 University of Helsinki, Department of Medical Genetics and Research Programme of Molecular Medicine, Biomedicum Helsinki, Finland

8 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK

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BMC Genomics 2008, 9:146  doi:10.1186/1471-2164-9-146

Published: 28 March 2008

Abstract

Background

The neuronal ceroid lipofuscinoses (NCL) are a group of children's inherited neurodegenerative disorders, characterized by blindness, early dementia and pronounced cortical atrophy. The similar pathological and clinical profiles of the different forms of NCL suggest that common disease mechanisms may be involved. To explore the NCL-associated disease pathology and molecular pathways, we have previously produced targeted knock-out mice for Cln1 and Cln5. Both mouse-models replicate the NCL phenotype and neuropathology; the Cln1-/- model presents with early onset, severe neurodegenerative disease, whereas the Cln5-/- model produces a milder disease with a later onset.

Results

Here we have performed quantitative gene expression profiling of the cortex from 1 and 4 month old Cln1-/- and Cln5-/- mice. Combined microarray datasets from both mouse models exposed a common affected pathway: genes regulating neuronal growth cone stabilization display similar aberrations in both models. 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; adenylate cyclase-associated protein 1 (Cap1), protein tyrosine phosphatase receptor type F (Ptprf) and protein tyrosine phosphatase 4a2 (Ptp4a2). The evidence from the gene expression data, indicating changes in the growth cone assembly, was substantiated by the immunofluorescence staining patterns of Cln1-/- and Cln5-/- cortical neurons. These primary neurons displayed abnormalities in cytoskeleton-associated proteins actin and β-tubulin as well as abnormal intracellular distribution of growth cone associated proteins GAP-43, synapsin and Rab3.

Conclusion

Our data provide the first evidence for a common molecular pathogenesis behind neuronal degeneration in INCL and vLINCL. Since CLN1 and CLN5 code for proteins with distinct functional roles these data may have implications for other forms of NCLs as well.