PMID- 10604467
OWN - NLM
STAT- MEDLINE
DCOM- 20000104
LR  - 20161124
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 402
IP  - 6762
DP  - 1999 Dec 9
TI  - Conversion of p35 to p25 deregulates Cdk5 activity and promotes
      neurodegeneration.
PG  - 615-22
AB  - Cyclin-dependent kinase 5 (Cdk5) is required for proper development of the
      mammalian central nervous system. To be activated, Cdk5 has to associate with its
      regulatory subunit, p35. We have found that p25, a truncated form of p35,
      accumulates in neurons in the brains of patients with Alzheimer's disease. This
      accumulation correlates with an increase in Cdk5 kinase activity. Unlike p35, p25
      is not readily degraded, and binding of p25 to Cdk5 constitutively activates
      Cdk5, changes its cellular location and alters its substrate specificity. In vivo
      the p25/Cdk5 complex hyperphosphorylates tau, which reduces tau's ability to
      associate with microtubules. Moreover, expression of the p25/Cdk5 complex in
      cultured primary neurons induces cytoskeletal disruption, morphological
      degeneration and apoptosis. These findings indicate that cleavage of p35,
      followed by accumulation of p25, may be involved in the pathogenesis of
      cytoskeletal abnormalities and neuronal death in neurodegenerative diseases.
FAU - Patrick, G N
AU  - Patrick GN
AD  - Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115,
      USA.
FAU - Zukerberg, L
AU  - Zukerberg L
FAU - Nikolic, M
AU  - Nikolic M
FAU - de la Monte, S
AU  - de la Monte S
FAU - Dikkes, P
AU  - Dikkes P
FAU - Tsai, L H
AU  - Tsai LH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Enzyme Activators)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (neuronal Cdk5 activator (p25-p35))
RN  - 0 (tau Proteins)
RN  - EC 2.7.11.1 (Cyclin-Dependent Kinase 5)
RN  - EC 2.7.11.22 (CDK5 protein, human)
RN  - EC 2.7.11.22 (Cdk5 protein, mouse)
RN  - EC 2.7.11.22 (Cdk5 protein, rat)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinases)
SB  - IM
CIN - Nature. 1999 Dec 9;402(6762):588-9. PMID: 10604460
MH  - 3T3 Cells
MH  - Aged
MH  - Aged, 80 and over
MH  - Alzheimer Disease/*enzymology/etiology/pathology
MH  - Animals
MH  - Apoptosis
MH  - Brain/enzymology
MH  - COS Cells
MH  - Cloning, Molecular
MH  - Culture Techniques
MH  - Cyclin-Dependent Kinase 5
MH  - Cyclin-Dependent Kinases/*metabolism
MH  - Cytoskeleton/metabolism/pathology
MH  - Enzyme Activation
MH  - Enzyme Activators/metabolism
MH  - Enzyme Stability
MH  - Female
MH  - Humans
MH  - Immunohistochemistry
MH  - Male
MH  - Matched-Pair Analysis
MH  - Mice
MH  - Middle Aged
MH  - Nerve Tissue Proteins/*metabolism
MH  - Neurofibrillary Tangles/enzymology
MH  - Neurons/pathology
MH  - Phosphorylation
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - tau Proteins/metabolism
EDAT- 1999/12/22 09:00
MHDA- 2001/03/23 10:01
CRDT- 1999/12/22 09:00
PHST- 1999/12/22 09:00 [pubmed]
PHST- 2001/03/23 10:01 [medline]
PHST- 1999/12/22 09:00 [entrez]
AID - 10.1038/45159 [doi]
PST - ppublish
SO  - Nature. 1999 Dec 9;402(6762):615-22. doi: 10.1038/45159.