Biomedical subjects

Carol M Troy

Publications and source records attributed to Carol M Troy.

7 recordsLinked to original sources

PubMed2006

Cell cycle molecules define a pathway required for neuron death in development and disease.

We review here evidence defining a molecular pathway that includes cell cycle-related molecules and that appears to play a required role in neuron death during normal development as well as in disease and trauma. The pathway starts with inappropriate activation of cyclin dependent kinase 4 (Cdk4) in neurons which leads to hyper-phosphorylation of the pRb family member p130. This in turn results in dissociation of p130 and its associated chromatin modifiers Suv39H1 and HDAC1 from the transcription factor E2F4. Dissociation of this complex results in de-repression of genes with E2F binding sites including those encoding the transcription factors B- and C-Myb. Once elevated in neurons, B- and C-Myb proteins bind to the promoter for the pro-apoptotic BH3-only protein Bim and promote its induction. Bim then interacts with the core cellular apoptotic machinery, leading to caspase activation and apoptotic death. This pathway is supported by a variety of observations and experimental findings that implicate it as a required element for neuron loss in development and in many nervous system traumas and disorders. The components of this pathway appear to represent potential therapeutic targets for prevention of disease-associated neuron death.

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PubMed2005

Caspase function in neuronal death: delineation of the role of caspases in ischemia.

Cerebral ischemia is one of the major causes of morbidity and mortality in the Western world. Despite extensive research, adequate therapies are still elusive. Neuronal degeneration and death are hallmarks of stroke/ischemia. Understanding how the death machinery executes neuronal death in ischemia will provide therapeutic targets. Key to the death machinery are caspases: the family of cell death proteases. While much data has been published regarding caspase involvement in models of ischemia, the pathways have not been thoroughly defined. The specification of the caspases critical for death has been hampered by the use of non-specific reagents. Thus many conclusions about specificity are unwarranted. In this review we discuss how caspases can be measured and review the existing knowledge of the roles of specific caspases in ischemia. We also discuss approaches to determining the molecules that execute ischemic death.

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PubMed2004

Highly efficient small interfering RNA delivery to primary mammalian neurons induces MicroRNA-like effects before mRNA degradation.

The study of protein function in neurons has been hindered by the lack of highly efficient, nontoxic methods of inducing RNA interference in such cells. Here we show that application of synthetic small interfering RNA (siRNA) linked to the vector peptide Penetratin1 results in rapid, highly efficient uptake of siRNA by entire populations of cultured primary mammalian hippocampal and sympathetic neurons. This treatment leads to specific knock-down of targeted proteins within hours without the toxicity associated with transfection. In contrast to current methods, our technique permits study of protein function across entire populations with minimal disturbance of complex cellular networks. Using this technique, we found that protein knock-down (evident after 6 hr) precedes any decrease in targeted message (evident after 24 hr), suggesting an early, translational repression by perfectly targeted siRNAs.

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PubMed2004

Balancing neuronal death.

Although it is apparent that neuronal death must be tightly regulated to ensure the proper development and mature functions of the nervous system, the molecular details of this regulation are not fully understood. In multiple neurodegenerative diseases, there is inappropriate death of cells in the nervous system. A better understanding of how death is regulated in the normal nervous system can provide a framework for determining how this regulation can go awry during neurodegenerative disease. The key executioners of neuronal apoptosis, the caspases, are regulated at several levels. The endogenous inhibitor of apoptosis family of proteins, the IAPs, can suppress caspase activity. In this Mini-Review, we examine what is known about the function of IAPs in normal neuronal function and in disease.

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PubMed2004

Divergence of the apoptotic pathways induced by 4-hydroxynonenal and amyloid beta-protein.

In this paper, we examine the hypothesis that 4-hydroxynonenal (HNE), a product of lipid peroxidation, is a key mediator of cell death resulting from beta-amyloid exposure. We revisit the effects of HNE on different neuronal cell types to determine which caspase or caspases are required for HNE-induced death, and to compare these results with the known caspase requirements in other death paradigms. We have previously shown that in a given neuronal cell type different death stimuli can evoke stimulus-specific apoptotic pathways. We now show that HNE treatment of neuronal cells induced dose-dependent death and caspase activity which were blocked by inhibition of caspases. Antisense down-regulation of caspases-3, -7 or -9 provided complete protection from HNE-induced death, as did down-regulation of the caspase regulators APAF-1 and DIABLO. Conversely, this work and our previous studies of three other death paradigms show that caspase-3 is not required for death induced by beta-amyloid, SOD1 down-regulation, or trophic factor deprivation. We also show that HNE accumulated in settings where death does not ensue. We conclude that HNE toxicity is mediated via a caspase-9-dependent pathway but that HNE accumulation need not induce cell death nor is it an obligate mediator of Abeta-induced cell death.

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PubMed2002

Caspases on the brain.

The basic mechanisms that underlie neurodegenerative diseases are unknown. Loss of function of specific regions of the brain is due to incapacitation of cells that constitute those regions. Cells can simply stop functioning normally (neurons may cease to transmit signals), or they may die. There is now evidence that the pathology of several neurodegenerative diseases is due to inappropriate apoptosis. This being the case, an understanding of the mediators of apoptosis, their identities, and their role in orchestrating death would be a vital step toward remedying the diseases. The central components of apoptotic pathways, proteases of the caspase family, are present in latent forms in all nucleated cells. Their activity is balanced by specific activation and inactivation events, and the molecular and biochemical controls have been well established in vitro and in model transformed cell lines. In this Mini-Review, we consider the current status of the basic control mechanisms and how these may be subverted during neurodegeneration.

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PubMed2002

Mechanisms of p75-mediated death of hippocampal neurons. Role of caspases.

Neurotrophins support neuronal survival and differentiation via Trk receptors, yet can also induce cell death via the p75 receptor. In these studies, we investigated signaling mechanisms governing p75-mediated death of hippocampal neurons, specifically the role of caspases. Although p75 is structurally a member of the Fas/TNFR1 receptor family, caspase-8 was not required for p75-mediated death, unlike other members of this receptor family. In contrast, p75-mediated neuronal death was associated with mitochondrial loss of cytochrome c and required Apaf-1 and caspase-9, -6, and -3. In particular, caspase-6 plays a central role in mediating neurotrophin-induced death, illuminating a novel role for this caspase. Inhibition of DIABLO/Smac, which blocks inhibitor of apoptosis proteins, protected cells from death, whereas simultaneous inhibition of both DIABLO/Smac and MIAP3 allowed trophin-induced death to proceed. In vivo, pilocarpine-induced seizures, previously shown to up-regulate p75 expression and increase neurotrophin production, caused activation of caspase-6 and -3 and cleavage of poly(ADP-ribose) polymerase in p75-expressing hippocampal neurons. In p75(-/-) mice, no activated caspase-3 was detected, and there was a marked reduction in the number of dying neurons after pilocarpine treatment compared with wild type mice. Neurotrophin-induced p75-mediated death is likely to play an important role in mediating neuronal loss consequent to brain injury.

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