Biomedical subjects

Andréa C LeBlanc

Publications and source records attributed to Andréa C LeBlanc.

5 recordsLinked to original sources

PubMed2006

Prion protein prevents Bax-mediated cell death in the absence of other Bcl-2 family members in Saccharomyces cerevisiae.

Although there is no consensus regarding the normal function of the prion protein, increasing evidence points towards a role in cellular protection against cell death. We have previously shown that prion protein is a potent inhibitor of Bax-induced apoptosis in human primary neurons and in the breast carcinoma MCF-7 cells. Here, we used the yeast Saccharomyces cerevisiae to investigate if the neuroprotective function of prion protein requires other members of the Bcl-2 family given that S. cerevisiae lacks Bcl-2 genes but undergoes a mitochondrial-dependent apoptotic cell death upon exogenous expression of Bax protein. We show that Bax induces cell death and growth inhibition in S. cerevisiae. Prion protein prevents Bax-mediated cell death. Prion protein overcomes Bax-mediated growth arrest in S phase but cannot overcome population growth inhibition because the cells then accumulate in G(2)/M phase. We conclude that prion protein does not require other Bcl-2 family proteins to protect against Bax-mediated cell death.

Animals↗

PubMed2004

Cellular prion protein neuroprotective function: implications in prion diseases.

Prion protein can display two conformations: a normal cellular conformation (PrP) and a pathological conformation associated with prion diseases (PrP(Sc)). Three complementary strategies are used by researchers investigating how PrP is involved in the pathogenesis of prion diseases: elucidation of the normal function of PrP, determination of how PrP(Sc) is toxic to neurons, and unraveling the mechanism for the conversion of PrP to PrP(Sc). We review the normal function of PrP as an antioxidant and an antiapoptotic protein in vivo and in vitro. This review also addresses contrasting evidence that PrP is cytotoxic. Finally, we discuss the implication of the neuroprotective role of PrP in prion diseases.

Animals↗

PubMed2004

Neuroprotective functions of prion protein.

The normal function of prion protein (PrP) is usually disregarded at the expense of the more fascinating role of PrP in transmissible prion diseases. However, the normal PrP may play an important role in cellular function in the central nervous system, since PrP is highly expressed in neurons and motifs in the sequence of PrP are conserved in evolution. The finding that prion null mice do not have a significant overt phenotype suggests that the normal function of PrP is of minor importance. However, the absence of PrP in cells or in vivo contributes to an increased susceptibility to oxidative stress or apoptosis-inducing insults. An alternative explanation is that the PrP normal function is so important that it is redundant. Probing into the characteristics of PrP has revealed a number of features that could mediate important cellular functions. The neuroprotective actions so far identified with PrP are initiated through cell surface signaling, antioxidant activity, or anti-Bax function. Here, we review the characteristics of the PrP and the evidence that PrP protects against neurodegeneration and neuronal cell death.

Animals↗

PubMed2003

Natural cellular inhibitors of caspases.

The crucial role of cell death in many diseases is obvious and has spurred intense research to understand the regulation of apoptotic pathways. Caspase activation is central to many of the apoptotic pathways. In recent years, the study of the regulation of caspase activation and activity in various cell lines and in diseases has revealed highly complex mechanisms regulating cell survival or cell death. In this review, the major natural cellular anticaspase factors are described with particular attention to the inhibitors that prevent active caspases from committing the cell to irreversible destruction. The major group of caspase inhibitors known is the inhibitor of apoptosis proteins (IAP) and this review describes the characteristics of IAP, regulation of IAP expression, and mechanisms of action of IAP. However, other proteins including Bcl-2 family members, heat shock proteins, caspase-like decoy, calpains and proteases, and lipid moieties in the form of phosphoinositides also can function as caspase inhibitors. The current knowledge of the inhibition of these non-IAP factors is described herein.

Animals↗

PubMed2002

Effect of tumor necrosis factor-alpha converting enzyme (TACE) and metalloprotease inhibitor on amyloid precursor protein metabolism in human neurons.

Tumor necrosis factor-alpha (TNF-alpha) is implicated in inflammatory processes and much effort is being directed at inhibiting the release of TNF-alpha for treatment of inflammatory conditions. In this context, the drug CP-661,631 has been developed to inhibit the TNF-alpha converting enzyme (TACE). However, TACE is also implicated in amyloid precursor protein secretion. Amyloid precursor protein (APP) undergoes constitutive and regulated secretion by alpha-secretase endoproteolytic cleavage within the amyloid beta peptide (Abeta) domain. Alternative cleavage at the N- and C-terminus of the Abeta domain by beta- and gamma-secretases results in the production of Abeta. In many cellular and in vivo animal models, increased secretion of APP results in a concomitant decrease in the production of Abeta suggesting that the two pathways are intricately linked. However, in human primary neuron cultures, increased APP secretion is not associated with a decrease in total Abeta production. To determine if the use of CP-661,631 may enhance amyloidogenic processing in human brain, we have assessed the effect of CP-661,631 on APP metabolism in primary cultures of human neurons. Our results show that CP-661,631 effectively prevents regulated APP secretion but does not increase total Abeta levels in human primary neuron cultures.

ADAM Proteins↗