Brain gene expression profiles of <it>Cln1 </it>and <it>Cln5 </it>deficient mice unravels common molecular pathways underlying neuronal degeneration in NCL diseases
<p>Abstract</p> <p>Background</p> <p>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...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2008-03-01
|
| Series: | BMC Genomics |
| Online Access: | http://www.biomedcentral.com/1471-2164/9/146 |
| _version_ | 1818382151485227008 |
|---|---|
| author | Gentile Massimiliano Cooper Jonathan D Kopra Outi Saharinen Juha von Schantz Carina Hovatta Iiris Peltonen Leena Jalanko Anu |
| author_facet | Gentile Massimiliano Cooper Jonathan D Kopra Outi Saharinen Juha von Schantz Carina Hovatta Iiris Peltonen Leena Jalanko Anu |
| author_sort | Gentile Massimiliano |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>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 <it>Cln1 </it>and <it>Cln5</it>. Both mouse-models replicate the NCL phenotype and neuropathology; the <it>Cln1-/- </it>model presents with early onset, severe neurodegenerative disease, whereas the <it>Cln5-/- </it>model produces a milder disease with a later onset.</p> <p>Results</p> <p>Here we have performed quantitative gene expression profiling of the cortex from 1 and 4 month old <it>Cln1-/- </it>and <it>Cln5-/- mice</it>. 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 <it>Cln1 </it>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 <it>Cln1-/- </it>and <it>Cln5-/- </it>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.</p> <p>Conclusion</p> <p>Our data provide the first evidence for a common molecular pathogenesis behind neuronal degeneration in INCL and vLINCL. Since <it>CLN1 </it>and <it>CLN5 </it>code for proteins with distinct functional roles these data may have implications for other forms of NCLs as well.</p> |
| first_indexed | 2024-12-14T02:45:55Z |
| format | Article |
| id | doaj.art-f198ca15b2e44459b98b20936cd0e94f |
| institution | Directory Open Access Journal |
| issn | 1471-2164 |
| language | English |
| last_indexed | 2024-12-14T02:45:55Z |
| publishDate | 2008-03-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Genomics |
| spelling | doaj.art-f198ca15b2e44459b98b20936cd0e94f2022-12-21T23:19:53ZengBMCBMC Genomics1471-21642008-03-019114610.1186/1471-2164-9-146Brain gene expression profiles of <it>Cln1 </it>and <it>Cln5 </it>deficient mice unravels common molecular pathways underlying neuronal degeneration in NCL diseasesGentile MassimilianoCooper Jonathan DKopra OutiSaharinen Juhavon Schantz CarinaHovatta IirisPeltonen LeenaJalanko Anu<p>Abstract</p> <p>Background</p> <p>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 <it>Cln1 </it>and <it>Cln5</it>. Both mouse-models replicate the NCL phenotype and neuropathology; the <it>Cln1-/- </it>model presents with early onset, severe neurodegenerative disease, whereas the <it>Cln5-/- </it>model produces a milder disease with a later onset.</p> <p>Results</p> <p>Here we have performed quantitative gene expression profiling of the cortex from 1 and 4 month old <it>Cln1-/- </it>and <it>Cln5-/- mice</it>. 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 <it>Cln1 </it>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 <it>Cln1-/- </it>and <it>Cln5-/- </it>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.</p> <p>Conclusion</p> <p>Our data provide the first evidence for a common molecular pathogenesis behind neuronal degeneration in INCL and vLINCL. Since <it>CLN1 </it>and <it>CLN5 </it>code for proteins with distinct functional roles these data may have implications for other forms of NCLs as well.</p>http://www.biomedcentral.com/1471-2164/9/146 |
| spellingShingle | Gentile Massimiliano Cooper Jonathan D Kopra Outi Saharinen Juha von Schantz Carina Hovatta Iiris Peltonen Leena Jalanko Anu Brain gene expression profiles of <it>Cln1 </it>and <it>Cln5 </it>deficient mice unravels common molecular pathways underlying neuronal degeneration in NCL diseases BMC Genomics |
| title | Brain gene expression profiles of <it>Cln1 </it>and <it>Cln5 </it>deficient mice unravels common molecular pathways underlying neuronal degeneration in NCL diseases |
| title_full | Brain gene expression profiles of <it>Cln1 </it>and <it>Cln5 </it>deficient mice unravels common molecular pathways underlying neuronal degeneration in NCL diseases |
| title_fullStr | Brain gene expression profiles of <it>Cln1 </it>and <it>Cln5 </it>deficient mice unravels common molecular pathways underlying neuronal degeneration in NCL diseases |
| title_full_unstemmed | Brain gene expression profiles of <it>Cln1 </it>and <it>Cln5 </it>deficient mice unravels common molecular pathways underlying neuronal degeneration in NCL diseases |
| title_short | Brain gene expression profiles of <it>Cln1 </it>and <it>Cln5 </it>deficient mice unravels common molecular pathways underlying neuronal degeneration in NCL diseases |
| title_sort | brain gene expression profiles of it cln1 it and it cln5 it deficient mice unravels common molecular pathways underlying neuronal degeneration in ncl diseases |
| url | http://www.biomedcentral.com/1471-2164/9/146 |
| work_keys_str_mv | AT gentilemassimiliano braingeneexpressionprofilesofitcln1itanditcln5itdeficientmiceunravelscommonmolecularpathwaysunderlyingneuronaldegenerationinncldiseases AT cooperjonathand braingeneexpressionprofilesofitcln1itanditcln5itdeficientmiceunravelscommonmolecularpathwaysunderlyingneuronaldegenerationinncldiseases AT kopraouti braingeneexpressionprofilesofitcln1itanditcln5itdeficientmiceunravelscommonmolecularpathwaysunderlyingneuronaldegenerationinncldiseases AT saharinenjuha braingeneexpressionprofilesofitcln1itanditcln5itdeficientmiceunravelscommonmolecularpathwaysunderlyingneuronaldegenerationinncldiseases AT vonschantzcarina braingeneexpressionprofilesofitcln1itanditcln5itdeficientmiceunravelscommonmolecularpathwaysunderlyingneuronaldegenerationinncldiseases AT hovattaiiris braingeneexpressionprofilesofitcln1itanditcln5itdeficientmiceunravelscommonmolecularpathwaysunderlyingneuronaldegenerationinncldiseases AT peltonenleena braingeneexpressionprofilesofitcln1itanditcln5itdeficientmiceunravelscommonmolecularpathwaysunderlyingneuronaldegenerationinncldiseases AT jalankoanu braingeneexpressionprofilesofitcln1itanditcln5itdeficientmiceunravelscommonmolecularpathwaysunderlyingneuronaldegenerationinncldiseases |