title: Brain gene expression profiles of Cln1 and Cln5 deficient mice unravels common molecular pathways underlying neuronal degeneration in NCL diseases.
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 beta-tubulin as well as abnormal intracellular distribution of growth cone associated proteins GAP-43, synapsin and Rab3.
  
  
  CONCLUSIONS
  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.
authors: National Public Health Institute and FIMM, Institute for Molecular Medicine, Helsinki, Finland. carina.von.schantz@ktl.fi
authors: Carina
authors: C
authors: von Schantz
authors: Juha
authors: J
authors: Saharinen
authors: Outi
authors: O
authors: Kopra
authors: Jonathan D
authors: JD
authors: Cooper
authors: Massimiliano
authors: M
authors: Gentile
authors: Iiris
authors: I
authors: Hovatta
authors: Leena
authors: L
authors: Peltonen
authors: Anu
authors: A
authors: Jalanko
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D019922:GAP-43 Protein / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D005838:Genotype; D020439:Growth Cones / Q000378:metabolism / Q000473:pathology*; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics* / Q000473:pathology; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics / Q000378:metabolism; D016704:Synapsins / Q000378:metabolism; D013869:Thiolester Hydrolases / Q000235:genetics*; D020692:rab3 GTP-Binding Proteins / Q000378:metabolism
chemical_list: C488572:Cln5 protein, mouse; D019922:GAP-43 Protein; D017874:Immediate-Early Proteins; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins; D016704:Synapsins; D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase; D017027:Protein Tyrosine Phosphatases; C111533:Ptp4a2 protein, mouse; C000709129:Ptprf protein, mouse; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D020692:rab3 GTP-Binding Proteins; D000262:Adenylyl Cyclases