PubMed Journals: Nature
Source: PMID: 10830966
⇦ ⇨ Nature. 2000 May 18;405(6784):360-4.
Neurotoxicity induces cleavage of p35 to
p25 by calpain.
Lee MS(1), Kwon YT, Li M, Peng J, Friedlander
RM, Tsai LH.
(1) Howard Hughes Medical Institute and
Department of Pathology, Harvard Medical School,
Boston, Massachusetts 02115, USA.
Cyclin-dependent kinase 5 (cdk5) and its
neuron-specific activator p35 are required
for neurite outgrowth and cortical lamination.
Proteolytic cleavage of p35 produces p25,
which accumulates in the brains of patients
with Alzheimer's disease. Conversion of
p35 to p25 causes prolonged activation and
mislocalization of cdk5. Consequently, the
p25/cdk5 kinase hyperphosphorylates tau,
disrupts the cytoskeleton and promotes the
death (apoptosis) of primary neurons. Here we
describe the mechanism of conversion of
p35 to p25. In cultured primary cortical
neurons, excitotoxins, hypoxic stress and
calcium influx induce the production of
p25. In fresh brain lysates, addition of
calcium can stimulate cleavage of p35 to
p25. Specific inhibitors of calpain, a
calcium-dependent cysteine protease, effectively
inhibit the calcium-induced cleavage of
p35. In vitro, calpain directly cleaves
p35 to release a fragment with relative
molecular mass 25,000. The sequence of the
calpain cleavage product corresponds precisely
to that of p25. Application of the amyloid
beta-peptide A beta(1-42) induces the conversion
of p35 to p25 in primary cortical neurons.
Furthermore, inhibition of cdk5 or calpain
activity reduces cell death in A beta-treated
cortical neurons. These observations indicate
that cleavage of p35 to p25 by calpain may
be involved in the pathogenesis of Alzheimer's
DOI: 10.1038/35012636 PMID: 10830966 [Indexed