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			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.

			Author Information
			(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
			disease.

			DOI: 10.1038/35012636 PMID: 10830966 [Indexed
			for MEDLINE]

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