Niemann-Pick disease type C yields possible clue for why cerebellar neurons do not form neurofibrillary tangles.
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.
Bu
Bitao
B
Department of Pathology, University of Washington, Seattle, 98195, USA.
Klunemann
Hans
H
Suzuki
Kinuko
K
Li
Jin
J
Bird
Thomas
T
Jin
Lee-Way
LW
Vincent
Inez
I
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D016874:Neurofibrillary Tangles / Q000378:metabolism* / Q000473:pathology; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011689:Purkinje Cells / Q000378:metabolism* / Q000473:pathology; D016875:tau Proteins / Q000172:deficiency*
D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D016875:tau Proteins