Opinion: What is the role of protein aggregation in neurodegeneration?

Neurodegenerative diseases typically involve deposits of inclusion bodies that contain abnormal aggregated proteins. Therefore, it has been suggested that protein aggregation is pathogenic. However, several lines of evidence indicate that inclusion bodies are not the main cause of toxicity, and probably represent a cellular protective response. Aggregation is a complex multi-step process of protein conformational change and accretion. The early species in this process might be most toxic, perhaps through the exposure of buried moieties such as main chain NH and CO groups that could serve as hydrogen bond donors or acceptors in abnormal interactions with other cellular proteins. This model implies that the pathogenesis of diverse neurodegenerative diseases arises by common mechanisms, and might yield common therapeutic targets.     

Why is metabolic labour divided in nitrification?

Winogradsky discovered in 1890 that nitrification is carried out in two consecutive steps by two distinct groups of bacteria: ammonia-oxidizing bacteria and nitrite-oxidizing bacteria. An explanation for this division of labour is offered based on the kinetic theory of optimal design of metabolic pathways, which postulates the existence of an optimal length for a pathway that maximizes the rate of ATP production. Shortening long pathways could, therefore, increase growth rate. However, this would reduce growth yield if the shorter pathway has fewer ATP-generating steps. High yields would be advantageous when bacteria grow in clonal clusters, as is typical for biofilms. It is postulated that bacteria that completely oxidize ammonia to nitrate exist in such environments.     

Why is algaculture still incipient in Brazil?

Macroalgae represent 26 % of the global production of cultivated organisms, with Gracilaria spp. representing 12 % of that production; Eucheuma spp. and Kappaphycus alvarezii account for 34 % of world’s algae production. Despite the potential for cultivating seaweed in Brazil, and with its more than 8000 km of coastline, there is neither marine algaculture nor detailed knowledge even among aquaculture farmers concerning the utility of algae in agriculture, industry, and gastronomy, with the result that algaculture represents only the smallest fraction of national aquaculture production. The main cultivated species of seaweed sold in Brazil include the exotic K. alvarezii and native species of Gracilaria that are grown on small scales and do not meet national industrial demands, which must be supplemented by imports. We discuss Brazilian algaculture here, pointing out some of the problems that restrict commercial production of algae in that country and offer solutions that could be shared with other nations.     

Why is regenerative capacity restricted in higher organisms?

Regenerative powers of higher organisms are quite restricted. The theory given here attributes this to a postulated incompatibility between regeneration and the storage of memory. A corollary is that the extent to which these two processes are present in any organism should be inversely correlated; a phylogenetic survey appears to bear this out. The “alternative strategy” model has interesting implications relating to the practical possibilities inherent in “epigenetic” theories of ageing and cancer; these are discussed in the appendix.     

Why is celiac disease so common in Ireland?

Celiac disease (gluten sensitive enteropathy) is a condition affecting the small bowel, characterized by permanent intolerance to dietary gluten, and giving rise to varying degrees of malabsorption and diarrhea. With the advent of sensitive screening tests, the condition is being increasingly diagnosed. Celiac disease is more common in the Irish and in those of Irish descent. Simoons (1978, 1981) hypothesized that the present-day prevalence of celiac disease across Europe is related to the interaction between genetic gradients, largely determined by the advance of agriculture, and historical patterns of cereal ingestion. This essay examines Simoons' hypothesis as it relates to Ireland, reviews the ethnic and genetic mix of those living on the island of Ireland and aspects of Irish dietary history, and considers how these factors may have combined to result in a high frequency of celiac disease.     

Why is liana abundance low in semiarid climates?

Lianas are abundant in seasonal tropical forests, where they avoid seasonal water stress presumably by accessing deep‐soil water reserves. Although lianas are favoured in seasonal environments, their occurrence and abundance are low in semiarid environments. We hypothesized that lianas do not tolerate the great water shortage in the soil and air characteristic of semiarid environments, which would increase the risk of embolism. We compared the rooting depth of coarse roots, leaf dynamics, leaf water potential (ψ_leaf), embolism resistance (P₅₀) and lethal levels of embolism (P₈₈) between congeneric lianas that occur with different abundances in two semiarid sites differing in soil characteristics and vapour pressure deficit in the air (VPD_air). Regardless of soil texture and depth, water availability was restricted to the rainy season. All liana species were drought deciduous and had superficial coarse roots (not deeper than 35 cm). P₅₀ varied from ?1.8 to ?2.49 MPa, and all species operated under narrow safety margins against catastrophic (P₅₀) and irreversible hydraulic failure (P₈₈), even during the rainy season. In short, lianas that occur in semiarid environments have lower resistance to cavitation and limit carbon fixation to the rainy season because of leaf fall in the early dry season. We suggest that leaf shedding and shallow roots impairing carbon gain and growth in the dry season may explain why liana abundance is lower in semiarid than in other seasonally dry environments.     

When is screening effective in reducing the death rate?

Periodic screening programs for the early detection of chronic diseases such as cancer and heart disease may not always lead to a reduction in the number of deaths from the disease. Some improvement is usually possible with the use of a more sensitive detection test, or by lowering the age for the first screening examination, or by decreasing the period between examinations. However, the extent of the reduction in deaths that is attainable with these changes is limited by the underlying biological behavior of the disease as well as by the rate at which the disease is detected without the screening examination, i.e., by the “natural history” of the disease. The effectiveness of a periodic screening program is derived as a function of this natural history, the period between examinations, the sensitivity of the detection test, the age at the first examination, and the age distribution of the rate of the disease initiation in the screened population. A detailed discussion is given of how these results might be used to estimate the effectiveness of any planned periodic screening program. The analysis of a simple example suggests that for some diseases decreasing the interval between screening examinations may not lead to a significant lowering of the death rate, i.e., there may be a natural lower bound on the screening period.     

Why is chitosan mucoadhesive?

Chitosan is a biocompatible and biodegradable amino polysaccharide, which is soluble in aqueous solutions at pH < 6.5. It has been widely used for developing drug delivery systems because of its excellent mucoadhesive properties. Although many studies report on chitosan being mucoadhesive, the nature of interactions between chitosan and mucin remains poorly defined. Here, we have examined the role of primary amino groups and the role of electrostatic attraction, hydrogen bonding, and hydrophobic effects on aggregation of gastric mucin in the presence of chitosan. Reducing the number of amino groups through their half acetylation results in expansion of chitosan's pH-solubility window up to pH 7.4 but also reduces its capacity to aggregate mucin. We demonstrated that electrostatic attraction forces between chitosan and gastric mucin can be suppressed in the presence of 0.2 mol/L sodium chloride; however, this does not prevent the aggregation of mucin particles in the presence of this biopolymer. The presence of 8 mol/L urea or 10% v/v ethanol in solutions also affects mucin aggregation in the presence of chitosan, demonstrating the role of hydrogen bonding and hydrophobic effects, respectively, in mucoadhesion.     

Correction to: Why is chlorophyll b only used in light-harvesting systems?

Journal of Plant Research - The article Why is chlorophyll b only used in light-harvesting systems.     

How is protein aggregation in amyloidogenic diseases modulated by biological membranes?

The fate of proteins with amyloidogenic properties depends critically on their immediate biochemical environment. However, the role of biological interfaces such as membrane surfaces, as promoters of pathological aggregation of amyloidogenic proteins, is rarely studied and only established for the amyloid-β protein (Aβ) involved in Alzheimer’s disease, and α-synuclein in Parkinsonism. The occurrence of binding and misfolding of these proteins on membrane surfaces, is poorly understood, not at least due to the two-dimensional character of this event. Clearly, the nature of the folding pathway for Aβ protein adsorbed upon two-dimensional aggregation templates, must be fundamentally different from the three-dimensional situation in solution. Here, we summarize the current research and focus on the function of membrane interfaces as aggregation templates for amyloidogenic proteins (and even prionic ones). One major aspect will be the relationship between membrane properties and protein association and the consequences for amyloidogenic products. The other focus will be on a general understanding of protein folding pathways on two-dimensional templates on a molecular level. Finally, we will demonstrate the potential importance of membrane-mediated aggregation for non-amphiphatic soluble amyloidogenic proteins, by using the SOD1 protein involved in the amyotrophic lateral sclerosis syndrome. Australian Society for Biophysics Special Issue: Metals and Membranes in Neuroscience.     

Rethinking protein aggregation and drug discovery in neurodegenerative diseases: Why we need to embrace complexity?

More than a century has passed since pathological protein aggregates were first identified in the brains of patients with neurodegenerative diseases (NDDs). Yet, we still do not have effective therapies to treat or slow the progression of these devastating diseases or diagnostics for early detection and monitoring disease progression. Herein, I reflect on recent findings that are challenging traditional views about the composition, ultrastructural properties, and diversity of protein pathologies in the brain, their mechanisms of formation and how we investigate and model pathological aggregation processes in the laboratory today. This article is an invitation to embrace the complexity of proteinopathies as an essential step to understanding the molecular mechanisms underpinning NDDs and to advance translational research and drug discovery in NDDs.     

Is arginine charged in a membrane?

“Charged” amino acids play countless important roles in protein structure and function. Yet when these side chains come into contact with membranes we do not fully understand their behavior. This is highlighted by a recent model of voltage-gated ion channel activity and translocon-based experiments that suggest small penalties to expose these side chains to lipids, opposing the prevailing view in membrane biophysics. Here we employ a side chain analog as well as a transmembrane helix model to determine the free energy as a function of protonation state and position for a lipid-exposed arginine (Arg) residue across a membrane. We observe high free energy barriers for both the charged and neutral states. Due to the stabilizing influence of membrane deformations for the protonated form, the Arg side chain experiences a pK_a shift of ≤4.5 units and remains mostly protonated. The cost for exposing Arg to lipid hydrocarbon is prohibitively high with implications for many membrane translocating processes and the activation mechanisms of voltage-gated ion channels.