Journal
NEUROBIOLOGY OF DISEASE
Volume 11, Issue 2, Pages 285-297Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1006/nbdi.2002.0551
Keywords
neurofibrillary tangle; neurodegeneration; Niemann-Pick disease type C; Alzheimer's disease; cerebellum; Purkinje neurons; hyperphosphorylated tau; cell cycle; cdc2
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Funding
- NIA NIH HHS [P50 AG 05136-16, AG12721] Funding Source: Medline
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It is unknown why cerebellar neurons resist neurofibrillary tangle (NFT) formation. In Niemann-Pick disease Type C (NPC), NFT-mediated neurodegeneration occurs throughout brain, but the cerebellum degenerates conspicuously without NFT. To understand why, we have studied markers of NFT pathogenesis in cerebellum from 17 NPC cases, all having abundant NFT in forebrain. Remarkably, we found that NPC cerebella display several early markers of NFT formation, i.e., hyperphosphorylated tau and an array of cell cycle regulators, suggesting that cerebellar neurons in NPC undergo similar modifications as other neurons that develop NFT. However, cerebellar neurons are deficient in tau, the building block of NFT, and this may be one reason for their inability to form NFT. Even without NFT, cerebellar neurodegeneration may be triggered by the inappropriate activation of the cell cycle cdc2 kinase, and the npc-1 murine model provides an opportunity to test this hypothesis. (C) 2002 Elsevier Science (USA).
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