A novel peptide inhibitor targeted to caspase-3 cleavage site of a proapoptotic kinase protein kinase C delta (PKCdelta) protects against dopaminergic neuronal degeneration in Parkinson's disease models - PubMed (original) (raw)

A novel peptide inhibitor targeted to caspase-3 cleavage site of a proapoptotic kinase protein kinase C delta (PKCdelta) protects against dopaminergic neuronal degeneration in Parkinson's disease models

Anumantha G Kanthasamy et al. Free Radic Biol Med. 2006.

Abstract

Oxidative stress and apoptosis are considered common mediators of many neurodegenerative disorders including Parkinson's disease (PD). Recently, we identified that PKCdelta, a member of the novel PKC isoform family, is proteolytically activated by caspase-3 to induce apoptosis in experimental models of PD [Eur. J. Neurosci. 18 (6):1387-1401, 2003; Antioxid. Redox Signal. 5 (5):609-620, 2003]. Since caspase-3 cleaves PKCdelta between proline and aspartate residues at the cleavage site 324DIPD327 to activate the kinase, we developed an irreversible and competitive peptide inhibitor, Z-Asp(OMe)-Ile-Pro-Asp(OMe)-FMK (z-DIPD-fmk), to mimic the caspase-3 cleavage site of PKCdelta and tested its efficacy against oxidative stress-induced cell death in PD models. Cotreatment of z-DIPD-fmk with the parkinsonian toxins MPP(+) and 6-OHDA dose dependently attenuated cytotoxicity, caspase-3 activation, and DNA fragmentation in a mesencephalic dopaminergic neuronal cell model (N27 cells). However, z-DIPD-fmk treatment did not block MPP(+)-induced increases in caspase-9 enzyme activity. The z-DIPD-fmk peptide was much more potent (IC50 6 microM) than the most widely used and commercially available caspase-3 inhibitor z-DEVD-fmk (IC50 18 microM). Additionally, z-DIPD-fmk more effectively blocked PKCdelta cleavage and proteolytic activation than the cleavage of another caspase-3 substrate, poly(ADP-ribose) polymerase (PARP). Importantly, the peptide inhibitor z-DIPD-fmk completely rescued TH(+) neurons from MPP(+)- and 6-OHDA-induced toxicity in mouse primary mesencephalic cultures. Collectively, these results demonstrate that the PKCdelta cleavage site is a novel target for development of a neuroprotective therapeutic strategy for PD.

PubMed Disclaimer

Cited by

Experimental subarachnoid hemorrhage in rats: comparison of two endovascular perforation techniques with respect to success rate, confounding pathologies and early hippocampal tissue lesion pattern.
Höllig A, Weinandy A, Nolte K, Clusmann H, Rossaint R, Coburn M. Höllig A, et al. PLoS One. 2015 Apr 13;10(4):e0123398. doi: 10.1371/journal.pone.0123398. eCollection 2015. PLoS One. 2015. PMID: 25867893 Free PMC article.
Proteolytic activation of proapoptotic kinase protein kinase Cδ by tumor necrosis factor α death receptor signaling in dopaminergic neurons during neuroinflammation.
Gordon R, Anantharam V, Kanthasamy AG, Kanthasamy A. Gordon R, et al. J Neuroinflammation. 2012 Apr 27;9:82. doi: 10.1186/1742-2094-9-82. J Neuroinflammation. 2012. PMID: 22540228 Free PMC article.
Differential nigral expression of bcl-2 protein family in the pure and common forms of Dementia with Lewy bodies: relevance for dopaminergic neuronal vulnerability.
Saldaña M, Aguilar E, Bonastre M, Marin C. Saldaña M, et al. J Neural Transm (Vienna). 2007;114(11):1469-77. doi: 10.1007/s00702-007-0765-x. Epub 2007 Jul 4. J Neural Transm (Vienna). 2007. PMID: 17641817
Role of proteolytic activation of protein kinase Cδ in the pathogenesis of prion disease.
Harischandra DS, Kondru N, Martin DP, Kanthasamy A, Jin H, Anantharam V, Kanthasamy AG. Harischandra DS, et al. Prion. 2014 Jan-Feb;8(1):143-53. doi: 10.4161/pri.28369. Prion. 2014. PMID: 24576946 Free PMC article.
Histone hyperacetylation up-regulates protein kinase Cδ in dopaminergic neurons to induce cell death: relevance to epigenetic mechanisms of neurodegeneration in Parkinson disease.
Jin H, Kanthasamy A, Harischandra DS, Kondru N, Ghosh A, Panicker N, Anantharam V, Rana A, Kanthasamy AG. Jin H, et al. J Biol Chem. 2014 Dec 12;289(50):34743-67. doi: 10.1074/jbc.M114.576702. Epub 2014 Oct 23. J Biol Chem. 2014. PMID: 25342743 Free PMC article.

A novel peptide inhibitor targeted to caspase-3 cleavage site of a proapoptotic kinase protein kinase C delta (PKCdelta) protects against dopaminergic neuronal degeneration in Parkinson's disease models - PubMed (original) (raw)