Human Molecular Genetics Advance Access published online on September 30, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh312
© 2004 by Oxford University Press
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1 Department of Medical Genetics and Molecular Medicine, University of Helsinki and National Public Health Institute, Biomedicum Helsinki PL 104, FIN-00300 Helsinki, Finland
* To whom correspondence should be addressed. E-mail: leena.peltonen{at}ktl.fi.
Neuronal ceroid lipofuscinoses (NCL) comprise the most common group of childhood encephalopathies caused by mutations in eight genetic loci, CLN1-CLN8. Here we have developed a novel mouse model for the human vLINCL (CLN5) by targeted deletion of exon 3 of the mouse Cln5 gene. The Cln5-/- mice showed loss of vision and accumulation of autofluorescent storage material in the central nervous system (CNS) and peripheral tissues without prominent brain atrophy. The ultrastructure of the storage material accurately replicated the abnormalities in human patients revealing mixture of lamellar profiles including fingerprint profiles as well as curvilinear and rectilinear bodies in electron microscopic analysis. Prominent loss of a subset of GABAergic interneurons in several brain areas was seen in Cln5-/- mice. Transcript profiling of the brains of Cln5-/- mice revealed altered expression in several genes involved in neurodegeneration, as well as in defense and immune response, typical of age-associated changes in the CNS. Downregulation of structural components of myelin was detected and this agrees well with the hypomyelination seen in the human vLINCL patients. In general, the progressive pathology of Cln5-/- brain mimics the symptoms of the corresponding neurodegenerative disorder in man. Since the Cln5-/- mice do not exhibit significant brain atrophy, these mice could serve as models for studies on molecular processes associated with advanced aging.
Article
A Mouse Model for Finnish Variant Late Infantile Neuronal Ceroid Lipofuscinosis, CLN5, reveals neuropathology associated with early aging
2 Department of Human Genetics, David Geffen School of Medicine at UCLA, Gonda Neuroscience and Genetics Research Center, Room 6506, Los Angeles, California 90095; Cedars-Sinai Medical Center, Davis Building, Department of Pediatrics and David Geffen School of Medicine at UCLA, Los Angeles, CA
3 Department of Medical Genetics and Molecular Medicine, University of Helsinki and National Public Health Institute, Biomedicum Helsinki PL 104, FIN-00300 Helsinki, Finland; Department of Human Genetics, David Geffen School of Medicine at UCLA, Gonda Neuroscience and Genetics Research Center, Room 6506, Los Angeles, California 90095
4 Department of Human Genetics, David Geffen School of Medicine at UCLA, Gonda Neuroscience and Genetics Research Center, Room 6506, Los Angeles, California 90095
5 Department of Human Genetics, David Geffen School of Medicine at UCLA, Gonda Neuroscience and Genetics Research Center, Room 6506, Los Angeles, California 90095; Department of Applied Biology, University of Helsinki, Finland
6 Childrens hospital, University of Helsinki, Finland
7 Erasmus Medical Center, Department of Clinical Genetics, Rotterdam, The Netherlands
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