Human Molecular Genetics Advance Access originally published online on September 30, 2004
Human Molecular Genetics 2004 13(23):2893-2906; doi:10.1093/hmg/ddh312
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Human Molecular Genetics, Vol. 13, No. 23 © Oxford University Press 2004; all rights reserved
A mouse model for Finnish variant late infantile neuronal ceroid lipofuscinosis, CLN5, reveals neuropathology associated with early aging
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1Department of Medical Genetics and Molecular Medicine, University of Helsinki and National Public Health Institute, Biomedicum Helsinki PL 104, FIN-00300 Helsinki, Finland, 2Department of Human Genetics, David Geffen School of Medicine at UCLA, Gonda Neuroscience and Genetics Research Center, Room 6506, Los Angeles, CA 90095, USA, 3Childrens hospital, University of Helsinki, Finland and 4Erasmus Medical Center, Department of Clinical Genetics, Rotterdam, The Netherlands
Received May 31, 2004; Accepted September 20, 2004
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 electronmicroscopic analysis. Prominent loss of a subset of GABAergic interneurons in several brain areas was seen in the Cln5–/– mice. Transcript profiling of the brains of the 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 the 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.
* To whom correspondence should be addressed at: Department of Molecular Medicine, National Public Health Institute, Biomedicum Helsinki PL 104, FIN-00251 Helsinki, Finland. Tel: +358 947448393; Fax: +358 947448480; Email: leena.peltonen{at}ktl.fi
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