Anti-apoptotic activity of the herpes simplex virus type 2 gene ICP10 PK: Implications for therapy of neurological disorders that involve apoptosis
AuthorPerkins, Dana Stela
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AbstractApoptosis is an etiologic component of neurodegenerative disorders [e.g. Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS)] and acute brain injury (ischemia/hypoxia and trauma). Our laboratory has previously shown that a Herpes Simplex Virus Type 2 (HSV-2) gene, ICP10 PK, activates the Ras/MEK/ERK pathway in non-neuronal cells. Because this pathway was implicated in neuronal cell survival, the present studies tested whether ICP 10 PK blocks apoptosis in various experimental paradigms of neuronal apoptosis: (1) virus infection of primary hippocampal cultures, (2) trophic factor deprivation of NGF-dependent PC12 cells and primary hippocampal cultures, (3) naturally occurring genetic disorders such as the mouse trisomy 16 (Ts16), and (4) oxidative stress of N2a neuronal cells that express a mutant superoxide dismutase-1 (G85R). In the virus infection paradigm, HSV-1 and an HSV-2 mutant deleted in ICP10 PK (ICP10DeltaPK) induced apoptosis, but apoptosis was not seen for HSV-2 and an HSV-2 mutant that retains the ICP10 PK (ICP10DeltaRR), suggesting that ICP10 PK has anti-apoptotic activity. This activity was dependent on activation of the Raf/MEK/ERK survival pathway and inhibition of the pro-apoptotic JNK/c-Jun pathway. It involved inhibition of caspase-3 activation and PARP cleavage, likely resulting from induction of the anti-apoptotic protein Bag-1 and inhibition of the pro-apoptotic protein Bad. Ectopically expressed ICP10 PK inhibited apoptosis in the three other tested paradigms. The broad anti-apoptotic activity of ICP10 PK suggests that it may be used in gene therapy of neurological disorders that involve apoptosis. A replication-deficient HSV-2 mutant (ICP10DeltaRR) engineered in our laboratory, was used for non-invasive delivery of ICP10 PK to the CNS. Expression of the therapeutic ICP10 PK gene following intranasal administration in the mouse, was consistent with a central spread of the vector through the central olfactory pathways to the hippocampus and related limbic structures. Collectively, the data suggest that ICP10 PK has broad anti-apoptotic activity and can be delivered to the CNS by peripheral administration of a replication-deficient HSV-2 vector.
DescriptionUniversity of Maryland, Baltimore. Pharmacology and Experimental Therapeutics. Ph.D. 2002
Herpesvirus 2, Human