How do neurons die in neurodegenerative diseases?

Given that neurons are post-mitotic cells, their life span is generally long enough to reach that of humans. However, sometimes neurons die without recognizable causes, as a result of a process called neurodegeneration. Apart from when gene mutations can be correlated with disease, it is difficult to pinpoint molecules that are responsible for neuronal death. Therefore, neurons living in a 'sick state' for many years might reveal important information about neuronal death. Systematic and extensive single-neuron analysis of 'sick' neurons is expected to provide clues to the mechanisms of neurodegeneration. Moreover, the elimination of putative triggering and promoting factors involved in neurodegenerative disease might prevent disease progression.     

γ-Glutamylamines and neurodegenerative diseases

Transglutaminases catalyze the formation of γ-glutamylamines utilizing glutamyl residues and amine-bearing compounds such as lysyl residues and polyamines. These γ-glutamylamines can be released from proteins by proteases in an intact form. The free γ-glutamylamines can be catabolized to 5-oxo-L-proline and the free amine by γ-glutamylamine cyclotransferase. Free γ-glutamylamines, however, accumulate in the CSF and affected areas of Huntington Disease brain. This observation suggests transglutaminase-derived γ-glutamylamines may play a more significant role in neurodegeneration than previously thought. The following monograph reviews the metabolism of γ-glutamylamines and examines the possibility that these species contribute to neurodegeneration.     

Amyloid in neurodegenerative diseases: friend or foe?

Accumulation of amyloid-like aggregates is a hallmark of numerous neurodegenerative disorders such as Alzheimer's and polyglutamine disease. Yet, whether the amyloid inclusions found in these diseases are toxic or cytoprotective remains unclear. Various studies suggest that the toxic culprit in the amyloid folding pathway is actually a soluble oligomeric species which might interfere with normal cellular function by a multifactorial mechanism including aberrant protein-protein interactions. Molecular chaperones suppress toxicity of amyloidogenic proteins by inhibiting aggregation of non-native disease substrates and targeting them for refolding or degradation. Paradoxically, recent studies also suggest a protective action of chaperones in their promotion of the assembly of large, tightly packed, benign aggregates that sequester toxic protein species.     

Does O-GlcNAc play a role in neurodegenerative diseases?

There are several lines of evidence that the modification of proteins by cytosolic- and nuclear-specific O-linked N-acetylglucosamine (O-GlcNAc) glycosylation is closely related to neuropathologies, particularly Alzheimer’s disease. Several neuronal proteins have been identified as being modified with O-GlcNAc; these proteins could form part of the inclusion bodies found, for example, in the most frequently observed neurologic disorder (i.e., Alzheimer’s disease; Tau protein and β-amyloid peptide are the well known aggregated proteins). O-GlcNAc proteins are also implicated in synaptosomal transport (e.g., synapsins and clathrin-assembly proteins). Inclusion bodies are partly characterized by a deficiency in the ubiquitin–proteasome system, avoiding the degradation of aggregated proteins. From this perspective, it appears interesting that substrate proteins could be protected against proteasomal degradation by being covalently modified with single N-acetylglucosamine on serine or threonine, and that the proteasome itself is modified and regulated by O-GlcNAc (in this case the turnover of neuronal proteins correlates with extracellular glucose). Interestingly, glucose uptake and metabolism are impaired in neuronal disorders, and this phenomenon is linked to increased phosphorylation. In view of the existence of the dynamic interplay between O-GlcNAc and phosphorylation, it is tempting to draw a parallel between the use of glucose, O-GlcNAc glycosylation and phosphorylation. Lastly, the two enzymes responsible for O-GlcNAc dynamism (i.e., O-GlcNAc transferase and glucosaminidase) are both enriched in the brain and genes that encode the two enzymes are located in two regions that are found to be frequently mutated in neurologic disorders. The data presented in this review strongly suggest that O-GlcNAc could play an active role in neurodegenerative diseases.     

Does O-GlcNAc play a role in neurodegenerative diseases?

There are several lines of evidence that the modification of proteins by cytosolic- and nuclear-specific O-linked N-acetylglucosamine (O-GlcNAc) glycosylation is closely related to neuropathologies, particularly Alzheimer's disease. Several neuronal proteins have been identified as being modified with O-GlcNAc; these proteins could form part of the inclusion bodies found, for example, in the most frequently observed neurologic disorder (i.e., Alzheimer's disease; Tau protein and beta-amyloid peptide are the well known aggregated proteins). O-GlcNAc proteins are also implicated in synaptosomal transport (e.g., synapsins and clathrin-assembly proteins). Inclusion bodies are partly characterized by a deficiency in the ubiquitin-proteasome system, avoiding the degradation of aggregated proteins. From this perspective, it appears interesting that substrate proteins could be protected against proteasomal degradation by being covalently modified with single N-acetylglucosamine on serine or threonine, and that the proteasome itself is modified and regulated by O-GlcNAc (in this case the turnover of neuronal proteins correlates with extracellular glucose). Interestingly, glucose uptake and metabolism are impaired in neuronal disorders, and this phenomenon is linked to increased phosphorylation. In view of the existence of the dynamic interplay between O-GlcNAc and phosphorylation, it is tempting to draw a parallel between the use of glucose, O-GlcNAc glycosylation and phosphorylation. Lastly, the two enzymes responsible for O-GlcNAc dynamism (i.e., O-GlcNAc transferase and glucosaminidase) are both enriched in the brain and genes that encode the two enzymes are located in two regions that are found to be frequently mutated in neurologic disorders. The data presented in this review strongly suggest that O-GlcNAc could play an active role in neurodegenerative diseases.     

What can humans learn from flies about adenomatous polyposis coli?

Somatic or inherited mutations in the adenomatous polyposis coli (APC) gene are a frequent cause of colorectal cancer in humans. APC protein has an important tumor suppression function to reduce cellular levels of the signaling protein beta-catenin and, thereby, inhibit beta-catenin and T-cell-factor-mediated gene expression. In addition, APC protein binds to microtubules in vertebrate cells and localizes to actin-rich adherens junctions in epithelial cells of the fruit fly Drosophila (Fig. 1). Very little is known, however, about the function of these cytoskeletal associations. Recently, Hamada and Bienz have described a potential role for Drosophila E-APC in cellular adhesion, which offers new clues to APC function in embryonic development, and potentially colorectal adenoma formation and tumor progression in humans.     

Is there a role for copper in neurodegenerative diseases?

Copper is an essential metal in living organisms; thus, the maintenance of adequate copper levels is of vital importance and is highly regulated. Dysfunction of copper metabolism leading to its excess or deficiency results in severe ailments. Two examples of illnesses related to alterations in copper metabolism are Menkes and Wilson diseases. Several proteins are involved in the maintenance of copper homeostasis, including copper transporters and metal chaperones. In the last several years, the beta-amyloid-precursor protein (beta-APP) and the prion protein (PrP(C)), which are related to the neurodegenerative disorders Alzheimer and prion diseases respectively, have been associated with copper metabolism. Both proteins bind copper through copper-binding domains that also have been shown to reduce copper in vitro. Moreover, this ability to reduce copper is associated with a neuroprotective effect exerted by the copper-binding domain of both proteins against copper in vivo. In addition to a functional link between copper and beta-APP or PrP(C), evidence suggests that copper has a role in Alzheimer and prion diseases. Here, we review the evidence that supports both, the role of beta-APP and PrP(C), in copper metabolism and the putative role of copper in neurodegenerative diseases.     

Modelling neurodegenerative diseases in Drosophila: a fruitful approach?

Human neurodegenerative diseases are characterized by the progressive loss of specific neuronal populations, resulting in substantial disability and early death. The identification of causative single-gene mutations in families with inherited neurodegenerative disorders has facilitated the modelling of these diseases in experimental organisms, including the fruitfly Drosophila melanogaster. Many neurodegenerative diseases have now been successfully modelled in Drosophila, and genetic analysis is under way in each of these models. Using fruitfly genetics to define the molecular pathways that underlie the neurodegenerative process is likely to improve substantially our understanding of the pathogenesis of the human diseases, and to provide new therapeutic targets.     

Can mammalian cloning combined with embryonic stem cell technologies be used to treat human diseases?

Cloning is commonly perceived as a means of generating genetically identical individuals, but it can also be used to obtain genetically matched embryo-derived stem cells, which could potentially be used in the treatment of patients. A recent report offers the first 'proof of principle' of such cloning for therapeutic purposes, referred to as nuclear transplantation to produce stem cells for autologous transplantation.     

Can biosensors help to protect drinking water?

A large proportion of drinking water is abstracted for treatment from lowland rivers—about 30% in the UK—and this water is at particular risk from sudden and poisonous industrial or agricultural pollution. To cover the range of potential pollutants it may be possible to use biosensors as broadband monitors for toxins. The underlying assumption is that some biological processes, when challenged with a toxin, will be affected in a way analogous to that of man, and that therefore on-line scrutiny of such processes will provide early warning of substances liable to be detrimental to human health. Suitable processes for study might involve multi-cellular organisms, whole cells or enzymes. To date, most practical work has concentrated on fish, but enzymes and single cells hold out the promise of quicker response and, possibly, easier maintenance.     

Can imperfections help to improve bioreactor performance?

Pilot-scale and larger bioreactors differ from small laboratory-scale reactors in terms of a greater occurrence of noise and incomplete mixing of the broth. Conventional control tries to induce good mixing and to filter out the noise as completely as possible. As such an 'ideal' operation is difficult to achieve, recent work has tried to exploit the non-ideal features to improve the performance. Using artificial neural networks, the degree of mixing, the extent of filtering of noise and the distribution of plasmid copy number (in a recombinant fermentation) can be controlled effectively on-line. This strategy generates better productivities than well-mixed noise-free operations, which suggests that deviations from ideal behaviour should be gainfully harnessed and not suppressed.     

Can mechanism help explain insect host choice?

Evolutionary theory predicts that herbivorous insects should lay eggs on plants in a way that reflects the suitability of each plant species for larval development. Empirical studies, however, often fail to find any relationship between an adult insect's choice of host-plant and offspring fitness, and in such cases, it is generally assumed that other 'missing' factors (e.g. predation, host-plant abundance, learning and adult feeding sites) must be contributing to overall host suitability. Here, I consider an alternative theory - that a fitness cost inherent in the olfactory mechanism could constrain the evolution of insect host selection. I begin by reviewing current knowledge of odour processing in the insect antennal lobe with the aid of a simple schematic: the aim being to explain the workings of this mechanism to scientists who do not have prior knowledge in this field. I then use the schematic to explore how an insect's perception of host and non-host odours is governed by a set of processing rules, or algorithm. Under the assumptions of this mechanistic view, the perception of every plant odour is interrelated, and seemingly bad host choices can still arise as part of an overall adaptive behavioural strategy. I discuss how an understanding of mechanism can improve the interpretation of theoretical and empirical studies in insect behaviour and evolution.     

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.