RT Journal Article
SR Electronic
T1 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
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 9117
OP 9126
DO 10.1523/JNEUROSCI.2729-04.2004
VO 24
IS 41
A1 Sleat, David E.
A1 Wiseman, Jennifer A.
A1 El-Banna, Mukarram
A1 Kim, Kwi-Hye
A1 Mao, Qinwen
A1 Price, Sandy
A1 Macauley, Shannon L.
A1 Sidman, Richard L.
A1 Shen, Michael M.
A1 Zhao, Qi
A1 Passini, Marco A.
A1 Davidson, Beverly L.
A1 Stewart, Gregory R.
A1 Lobel, Peter
YR 2004
UL http://www.jneurosci.org/content/24/41/9117.abstract
AB 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.