Sex and death: what is the connection?

A cost of reproduction, where lifespan and fecundity are negatively correlated, is of widespread occurrence. Mutations in insulin/IGF signaling (IIS) pathways and dietary restriction (DR) can extend lifespan in model organisms but do not always reduce fecundity, suggesting that the link between lifespan and fecundity is not inevitable. Understanding the molecular basis of the cost of reproduction will be informed by elucidation of the mechanisms by which DR and IIS affect these two traits.     

Autophagy and apoptosis: what is the connection?

The therapeutic potential of autophagy for the treatment cancer and other diseases is beset by paradoxes stemming from the complexity of the interactions between the apoptotic and autophagic machinery. The simplest question of how autophagy acts as both a protector and executioner of cell death remains the subject of substantial controversy. Elucidating the molecular interactions between the processes will help us understand how autophagy can modulate cell death, whether autophagy is truly a cell death mechanism, and how these functions are regulated. We suggest that, despite many connections between autophagy and apoptosis, a strong causal relationship wherein one process controls the other, has not been demonstrated adequately. Knowing when and how to modulate autophagy therapeutically depends on understanding these connections.     

Oxidative stress and Alzheimer disease: the autophagy connection?

Intraneuronal accumulation of amyloid beta-protein (Abeta) is believed to be responsible for degeneration and apoptosis of neurons and consequent senile plaque formation in Alzheimer disease (AD), the main cause of senile dementia. Oxidative stress, an early determinant of AD, has been recently found to induce intralysosomal Abeta accumulation in cultured differentiated neuroblastoma cells through activation of macroautophagy. Because Abeta is known to destabilize lysosomal membranes, potentially resulting in apoptotic cell death, this finding suggests the involvement of oxidative stress-induced macroautophagy in the pathogenesis of AD.     

Glycation,glycolysis, and neurodegenerative diseases: Is there any connection?

This review considers the interrelation between different types of protein glycation, glycolysis, and the development of amyloid neurodegenerative diseases. The primary focus is on the role of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase in changing the concentration of carbonyl compounds – first and foremost, glyceraldehyde-3-phosphate and methylglyoxal. It has been suggested that various modifications of the enzyme – from the oxidation of the sulfhydryl groups of the active site to glycation with sugars – can lead to its inactivation, which causes a direct increase in glyceraldehyde-3-phosphate concentration and an indirect increase in the content of other aldehydes. This “primary inactivation” of glyceraldehyde-3-phosphate dehydrogenase promotes its glycation with aldehydes, including its own substrate, and a further irreversible decrease in its activity. Such a cycle can lead to numerous consequences – from the induction of apoptosis, which is activated by modified forms of the enzyme, to glycation of amyloidogenic proteins by glycolytic aldehydes. Of particular importance during the inhibition of glyceraldehyde-3-phosphate dehydrogenase is an increase in the content of the glycating compound methylglyoxal, which is much more active than reducing sugars (glucose, fructose, and others). In addition, methylglyoxal is formed by two pathways – in the cascade of reactions during glycation and from glycolytic aldehydes. The ability of methylglyoxal to glycate proteins makes it the main participant in this protein modification. We consider the effect of glycation on the pathological transformation of amyloidogenic proteins and peptides – β-amyloid peptide, α-synuclein, and prions. Our primary focus is on the glycation of monomeric forms of these proteins with methylglyoxal, although most works are dedicated to the analysis of the presence of “advanced glycation end products” in the already formed aggregates and fibrils of amyloid proteins. In our opinion, the modification of aggregates and fibrils is secondary in nature and does not play an important role in the development of neurodegenerative diseases. The glycation of amyloid proteins with carbonyl compounds can be one of the triggers of their transformation into toxic forms. The possible role of glycation of amyloidogenic proteins in the prevention of their modification by ubiquitin and the SUMO proteins due to a disruption of their degradation is separately considered.     

Actin-related protein 1 and cytoplasmic dynein-based motility - what's the connection?

The actin-related protein Arp1 works in conjunction with the microtubule-based motor cytoplasmic dynein to drive many types of intracellular motility. In vertebrate cells, Arp1 is present exclusively in the form of a 37-nm filament that constitutes the backbone of dynactin, a 1.2-MDa macromolecular complex containing nine other polypeptides. Dynactin has been proposed to function as the link between dynein and its cargo. Recent work indicates that the dynactin subunit p150(Glued) mediates the interaction of the dynactin molecule with dynein and microtubules, leaving the Arp1 filament as a possible cargo-binding domain. Mechanisms for binding of F-actin to membranes are discussed as models of the Arp1-membrane interaction.     

Obesity and the rate of time preference: is there a connection?

It is hypothesized that recent trends in US and worldwide obesity are, in part, related to an increase in the marginal rate of time preference, where time preference refers to the rate at which people are willing to trade current benefit for future benefit. The higher the rate of time preference, the larger is the factor by which individuals discount the future health risks associated with current consumption. Data from the United States, as well as international evidence, suggest that a relationship between these two variables is plausible. The authors encourage researchers to explore the possible link between obesity and time preference, as important insights are likely to result.     

Mitochondrial morphology and protein import--a tight connection?

Although the field of mitochondrial protein import and assembly may have initially been viewed as a completely distinct area of investigation to that of mitochondrial morphology and dynamics, recent findings have noted a clear influence on organelle morphology by perturbations in protein import pathways. This review aims to provide an overview of the mitochondrial import machinery in context of the recent link between translocation components and organelle structure, in addition to conferring the questions and challenges that have surfaced due to these observations.     

Fungal virulence, vertebrate endothermy, and dinosaur extinction: is there a connection?

Fungi are relatively rare causes of life-threatening systemic disease in immunologically intact mammals despite being frequent pathogens in insects, amphibians, and plants. Given that virulence is a complex trait, the capacity of certain soil fungi to infect, persist, and cause disease in animals despite no apparent requirement for animal hosts in replication or survival presents a paradox. In recent years studies with amoeba, slime molds, and worms have led to the proposal that interactions between fungi and other environmental microbes, including predators, select for characteristics that are also suitable for survival in animal hosts. Given that most fungal species grow best at ambient temperatures, the high body temperature of endothermic animals must provide a thermal barrier for protection against infection with a large number of fungi. Fungal disease is relatively common in birds but most are caused by only a few thermotolerant species. The relative resistance of endothermic vertebrates to fungal diseases is likely a result of higher body temperatures combined with immune defenses. Protection against fungal diseases could have been a powerful selective mechanism for endothermy in certain vertebrates. Deforestation and proliferation of fungal spores at cretaceous-tertiary boundary suggests that fungal diseases could have contributed to the demise of dinosaurs and the flourishing of mammalian species.     

Chromatin: a connection between loops and barriers?

A genetic screen for proteins that can block the spread of silenced heterochromatin has identified components of the nuclear pores with potential barrier activity. These results suggest that formation of loops of chromatin anchored to the pore could be one mechanism of barrier function.