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.

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. Research Abstract Details 

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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. Abstract Text:

Anumantha G Kanthasamy,Vellareddy Anantharam,Danhui Zhang,Calivarathan Latchoumycandane,Huajun Jin,Siddharth Kaul,Arthi Kanthasamy,

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.

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. Publishing Authors By Initials

AG Kanthasamy,V Anantharam,D Zhang,C Latchoumycandane,H Jin,S Kaul,A Kanthasamy,

For similar enzymes and coenzymes: enzymes: oxidoreductases: oxygenases: mixed function oxygenases: tyrosine 3-monooxygenase research abstracts see: enzymes and coenzymes: enzymes: oxidoreductases: oxygenases: mixed function oxygenases: tyrosine 3-monooxygenase research

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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. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Free radical biology & medicine

VOLUME: 41

Page Numbers: 1578-89

Journal Abbreviation: Free Radic. Biol. Med.

ISSN: 0891-5849

DAY: 25

MONTH: 08

YEAR: 2006

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. Information

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LANGUAGE: eng

NlmUniqueID: 8709159

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. Keywords Mesh Terms:

KEYWORDS: Tyrosine 3-Monooxygenase

MESH TERMS: metabolism

Chemical & Substance for Abstract: 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. Information

Substance Name: Caspase 9

Registry Number: EC 3.4.22.-

Grant and Affiliation Information for 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.

AFFILIATION: Parkinson's Disorder Research Laboratory, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, 2008 Veterinary Medicine Building, Iowa State University, Ames, IA 50011-1250, USA. akanthas@iastate.edu

Country: United States

AGENCY: United States NINDS

GRANT: NS 38644

ACRONYM: NS

MEDLINETA: Free Radic Biol Med

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