Showing papers by "Valina L. Dawson published in 2002"

Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor.

Abstract: Poly(ADP-ribose) polymerase-1 (PARP-1) protects the genome by functioning in the DNA damage surveillance network. PARP-1 is also a mediator of cell death after ischemia-reperfusion injury, glutamate excitotoxicity, and various inflammatory processes. We show that PARP-1 activation is required for translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus and that AIF is necessary for PARP-1–dependent cell death. N -methyl- N ′-nitro- N -nitrosoguanidine, H2O2, and N -methyl-d-aspartate induce AIF translocation and cell death, which is prevented by PARP inhibitors or genetic knockout of PARP-1, but is caspase independent. Microinjection of an antibody to AIF protects against PARP-1–dependent cytotoxicity. These data support a model in which PARP-1 activation signals AIF release from mitochondria, resulting in a caspase-independent pathway of programmed cell death.

Apoptosis-inducing factor is involved in the regulation of caspase-independent neuronal cell death

Abstract: Caspase-independent death mechanisms have been shown to execute apoptosis in many types of neuronal injury. P53 has been identified as a key regulator of neuronal cell death after acute injury such as DNA damage, ischemia, and excitotoxicity. Here, we demonstrate that p53 can induce neuronal cell death via a caspase-mediated process activated by apoptotic activating factor-1 (Apaf1) and via a delayed onset caspase-independent mechanism. In contrast to wild-type cells, Apaf1-deficient neurons exhibit delayed DNA fragmentation and only peripheral chromatin condensation. More importantly, we demonstrate that apoptosis-inducing factor (AIF) is an important factor involved in the regulation of this caspase-independent neuronal cell death. Immunofluorescence studies demonstrate that AIF is released from the mitochondria by a mechanism distinct from that of cytochrome-c in neurons undergoing p53-mediated cell death. The Bcl-2 family regulates this release of AIF and subsequent caspase-independent cell death. In addition, we show that enforced expression of AIF can induce neuronal cell death in a Bax- and caspase-independent manner. Microinjection of neutralizing antibodies against AIF significantly decreased injury-induced neuronal cell death in Apaf1-deficient neurons, indicating its importance in caspase-independent apoptosis. Taken together, our results suggest that AIF may be an important therapeutic target for the treatment of neuronal injury.

Neuroprotective and neurorestorative strategies for Parkinson's disease.

Abstract: Advances in understanding the molecular mechanisms of cell death and the pathogenesis of sporadic and familial Parkinson's disease are creating new opportunities for the development of neuroprotective and/or neurorestorative therapies. Here we review many of these advances, highlighting areas and strategies that might be particularly suited to the development of innovative approaches that prevent degeneration and/or restore function in Parkinson's disease.

Poly(ADP-Ribose) Polymerase Impairs Early and Long-Term Experimental Stroke Recovery

Abstract: Background and Purpose— Poly(ADP-ribose) polymerase (PARP-1; Enzyme Commission 2.4.30) is a nuclear DNA repair enzyme that mediates early neuronal ischemic injury. Using novel 3-dimensional, fast spin-echo-based diffusion-weighted imaging, we compared acute (21 hours) and long-term (3 days) ischemic volume after middle cerebral artery (MCA) occlusion in PARP-1-null mutants (PARP−/−) versus genetically matched wild-type mice (WT mice). PARP−/− mice were also treated with viral transfection of wild-type PARP-1 to determine whether protection from MCA occlusion is lost with restoration of the gene product. Methods— Halothane-anesthetized mice were treated with reversible MCA occlusion via intraluminal suture technique. Ischemic volumes were delineated by diffusion-weighted imaging with high spatial and temporal resolution during MCA occlusion and reperfusion. Recombinant Sindbis virus carrying β-galactosidase (lacZ) or PARP-1 was injected into ipsilateral striatum, then animals underwent MCA occlusion 3 days...

A novel in vivo post-translational modification of p53 by PARP-1 in MPTP-induced parkinsonism.

Abstract: Sporadic Parkinson's disease (PD) affects primarily dopaminergic neurons of the substantia nigra pars compacta. There is evidence of necrotic and apoptotic neuronal death in PD, but the mechanisms behind selected dopaminergic neuronal death remain unknown. The tumor suppressor protein p53 functions to selectively destroy stressed or abnormal cells during life and development by means of necrosis and apoptosis. Activation of p53 leads to death in a variety of cells including neurons. p53 is a target of the nuclear enzyme Poly(ADP-ribose)polymerase (PARP), and PARP is activated following DNA damage that occurs following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. MPTP is the favored in vivo model of PD, and reproduces the pathophysiology, anatomy and biochemistry of PD. p53 protein normally exhibits a fleeting half-life, and regulation of p53 stability and activation is achieved mainly by post-translational modification. We find that p53 is heavily poly(ADP-ribosyl)ated by PARP-1 following MPTP intoxication. This post-translational modification serves to stabilize p53 and alters its transactivation of downstream genes. These influences of PARP-1 on p53 may underlie the mechanisms of MPTP-induced parkinsonism and other models of neuronal death.

The genetics of Parkinson’s disease

Abstract: The recent identification of several genes and gene loci linked to familial forms of Parkinson’s disease (PD) has contributed significantly to our understanding of the genetic contribution in PD. Although the etiology of sporadic PD remains unknown, it is currently assumed that genetic susceptibilities may be involved. The advent of genome-wide scanning techniques has now made it possible to conduct complete genome screens for linkage in PD in multigenerational parkinsonian kindreds. Such studies undoubtedly will be instrumental in establishing the susceptibility genes involved in idiopathic PD. This article reviews the recent advances in the genetics of PD.

The Orphan Nuclear Receptor, Steroidogenic Factor 1, Regulates Neuronal Nitric Oxide Synthase Gene Expression in Pituitary Gonadotropes

Abstract: Steroidogenic factor 1 (SF-1), an essential nuclear receptor, plays key roles in steroidogenic cell function within the adrenal cortex and gonads. It also contributes to reproductive function at all three levels of the hypothalamic-pituitary-gonadal axis. SF-1 regulates genes in the steroidogenic pathway, such as LHβ, FSHβ, and steroid hydroxylase. Abundant evidence suggests that nitric oxide (NO) has an important role in the control of reproduction due to its ability to control GnRH secretion from the hypothalamus and the preovulatory LH surge in pituitary gonadotropes. Recently, we cloned and characterized the promoter of mouse neuronal NO synthase (nNOS). nNOS is localized at all three levels of the hypothalamic-pituitary-gonadal axis to generate NO. We find that its major promoter resides at exon 2 in the pituitary gonadotrope αT3–1 cell line and that there is a nuclear hormone receptor binding site in this region, to which SF-1 can bind and regulate nNOS transcription. Mutation of the nuclear hormone...

Blocking Nitric Oxide Toxicity

Abstract: Nitric oxide (NO) is a novel neuronal messenger molecule which can mediate rapid signaling, diffusing freely in three dimensions to act throughout local regions of neural tissue (Garthwaite and Boulton 1995; Yun et al 1996) NO and other nitrogen oxides are derived from chemical reactions following NOS activation NO production can regulate ion channel activity, neurotransmitter release, cerebral blood flow, synaptic plasticity, growth cone structure, and gene expression in the nervous system NO can elicit such diverse cellular signaling due to a wide variety of molecular targets including soluble guanylate cyclase, other heme-containing enzymes including cyclooxygenase, thiol moieties and tyrosine residues on proteins, iron sulfur-containing proteins, and superoxide anion Thus, NO is important in normal neuronal signaling; however, when NO production is unregulated or excessive, NO can mediate neuronal degeneration NO has been implicated in the neuropathology of stroke, trauma, AIDS dementia, Alzheimer’s disease, multiple sclerosis, as well as bacterial and viral encephalitis (Dawson and Snyder 1994; Meldrum 1996) Limiting NO production under pathologic conditions has become a potentially important therapeutic target for the treatment of various neurologic diseases and disorders