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Calpains-mediated pten cleavage in excitotoxic neuronal death

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posted on 2014-10-01, 00:00 authored by M J Chen, P C Benjamin Soo, M S Choy, Z F Peng, H C Cheng, Steve Cheung
The tumor suppressor PTEN (phosphatase and tensin homolog deleted from chromosome 10) has been implicated in the pathogenesis of numerous neurodegenerative diseases, and is particularly noted for its inhibition of the pro-survival PI3K-Akt pathway. Excitotoxicity due to over-stimulation of ionotropic glutamate receptors in neurons are known to contribute to neurodegenerative diseases such as Alzheimer's disease and ischemic stroke. Previously we have demonstrated that the proteasomal inhibitor, lactacystin, induced cleavage of PTEN to a truncated 50kDa fragment which accumulates to the detergent-insoluble membrane fraction of the neuronal cells. Herein, we report that overstimulation of the ionotropic glutamate receptors with excess NMDA while causing induction of calpains activation in cultured cortical neurons results in the formation of a novel truncated PTEN fragment of molecular weight < 50kDa. In vitro cleavage assay further confirmed that calpains-mediated cleavage is responsible for the expression of < 50kDa, while the 50kDa PTEN fragment observed in latacystin-mediated neuronal death is held accountable by caspase-3 activation. Both truncated PTEN fragments preferentially partition to the detergent-insoluble fraction of neuronal cells. The fragments did not react with the phospho-specific PTEN antibody targeting the Cterminal regulatory serine and threonine residues, suggesting that the cleavage sites are localised at the C-terminal tail or the cleavage enhances dephosphorylation of these Cterminal regulatory sites. Future investigation to define the function and regulation of calpain- and caspase 3-generated truncated PTEN fragment will shed light on the role of PTEN in proteasome inhibition- and excitotoxicity-induced neuronal death in neurological diseases.

History

Title of book

Biochemistry and molecular biology coming of age

Series

Biochemistry Research Trends

Chapter number

1

Pagination

3 - 18

Publisher

Nova Science Publishers

Place of publication

Hauppage, N.Y.

ISBN-13

9781633218178

Language

eng

Publication classification

B Book chapter; B1.1 Book chapter

Copyright notice

2014, Nova Science Publishers

Extent

18

Editor/Contributor(s)

M Miu

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