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The Journal of Neuroscience, October 13, 2004, 24(41):9117-9126; doi:10.1523/JNEUROSCI.2729-04.2004

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Neurobiology of Disease
A Mouse Model of Classical Late-Infantile Neuronal Ceroid Lipofuscinosis Based on Targeted Disruption of the CLN2 Gene Results in a Loss of Tripeptidyl-Peptidase I Activity and Progressive Neurodegeneration

David E. Sleat,^1,2 Jennifer A. Wiseman,¹ Mukarram El-Banna,¹ Kwi-Hye Kim,¹ Qinwen Mao,⁴ Sandy Price,¹ Shannon L. Macauley,⁵ Richard L. Sidman,⁶ Michael M. Shen,^1,3 Qi Zhao,⁵ Marco A. Passini,⁵ Beverly L. Davidson,⁴ Gregory R. Stewart,⁵ and Peter Lobel^1,2

¹Center for Advanced Biotechnology and Medicine, and Departments of ²Pharmacology and ³Pediatrics, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854, ⁴Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa 52242, ⁵Genzyme Corporation, Framingham, Massachusetts 01701, and ⁶Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115

Mutations in the CLN2 gene, which encodes a lysosomal serine protease, tripeptidyl-peptidase I (TPP I), result in an autosomal recessive neurodegenerative disease of children, classical late-infantile neuronal ceroid lipofuscinosis (cLINCL). cLINCL is inevitably fatal, and there currently exists no cure or effective treatment. In this report, we provide the characterization of the first CLN2-targeted mouse model for cLINCL. CLN2-targeted mice were fertile and apparently healthy at birth despite an absence of detectable TPP I activity. At 7 weeks of age, neurological deficiencies became evident with the onset of a tremor that became progressively more severe and was eventually accompanied by ataxia. Lifespan of the affected mice was greatly reduced (median survival, 138 d), and extensive neuronal pathology was observed including a prominent accumulation of cytoplasmic storage material within the lysosomal-endosomal compartment, a loss of cerebellar Purkinje cells, and widespread axonal degeneration. The CLN2-targeted mouse therefore recapitulates much of the pathology and clinical features of cLINCL and represents an animal model that should provide clues to the normal cellular function of TPP I and the pathogenic processes that underlie neuronal death in its absence. In addition, the CLN2-targeted mouse also represents a valuable model for the evaluation of different therapeutic strategies.

Key words: cerebellum; degeneration; enzyme; epilepsy; lysosome; neuropathology; proteolysis

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Received May 19, 2004; revised August 3, 2004; accepted August 3, 2004.

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