Journal Article

A mouse model for Finnish variant late infantile neuronal ceroid lipofuscinosis, CLN5, reveals neuropathology associated with early aging

Outi Kopra, Jouni Vesa, Carina von Schantz, Tuula Manninen, Helena Minye, Anna-Liisa Fabritius, Juhani Rapola, Otto P. van Diggelen, Janna Saarela, Anu Jalanko and Leena Peltonen

in Human Molecular Genetics

Volume 13, issue 23, pages 2893-2906
Published in print December 2004 | ISSN: 0964-6906
Published online September 2004 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddh312
A mouse model for Finnish variant late infantile neuronal ceroid lipofuscinosis, CLN5, reveals neuropathology associated with early aging

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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.

Journal Article.  7521 words.  Illustrated.

Subjects: Genetics and Genomics

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