Showing papers by "David A. Pearce published in 2008"

Immune system irregularities in lysosomal storage disorders

Abstract: Lysosomal storage disorders (LSDs) are genetically inherited diseases characterized by the accumulation of disease-specific biological materials such as proteolipids or metabolic intermediates within the lysosome. The lysosomal compartment’s central importance to normal cellular function can be appreciated by examining the various pathologies that arise in LSDs. These disorders are invariably fatal, and many display profound neurological impairment that begins in childhood. However, recent studies have revealed that several LSDs also have irregularities in the function of the immune system. Gaucher disease, mucopolysaccharidosis VII, and α-mannosidosis are examples of a subset of LSD patients that are predisposed towards immune suppression. In contrast, GM2 gangliosidosis, globoid cell leukodystrophy, Niemann-Pick disease type C1 and juvenile neuronal ceroid lipofuscinosis are LSDs that are predisposed towards immune system hyperactivity. Antigen presentation and processing by dedicated antigen presenting cells (APCs), secretion of pore-forming perforins by cytotoxic-T lymphocytes, and release of pro-inflammatory mediators by mast cells are among the many crucial immune system functions in which the lysosome plays a central role. Although the relationship between the modification of the lysosomal compartment in LSDs and modulation of the immune system remains unknown, there is emerging evidence for early neuroimmune responses in a variety of LSDs. In this review we bridge biochemical studies on the lysosomal compartment’s role in the immune system with clinical data on immune system irregularities in a subset of LSDs.

Transcript and in silico analysis of CLN3 in juvenile neuronal ceroid lipofuscinosis and associated mouse models

Abstract: Juvenile neuronal ceroid lipofuscinoses (JNCL), commonly known as Batten disease, is a progressive neurodegenerative disorder of childhood characterized by blindness, seizures, motor and cognitive decline, leading to death in early adulthood. Mutations within the CLN3 gene, which encodes a putative lysosomal protein of unknown function, are the underlying cause of JNCL. Over 85% of JNCL patients harbor a 1 kb deletion that is predicted to result in a truncated CLN3 protein and is presumed to be a null mutation. A recent study by Kitzmuller et al. ( 1) suggested that the 1 kb deletion-associated truncated protein may have partial function, and proposed that JNCL is a mutation-specific disease. In addition, the validity of the original and most widely utilized JNCL mouse model, the Cln3Δex1-6 mouse, as a true null mutant was questioned. We report a substantial decrease in the transcript level of the truncated CLN3 gene product in cells from 1 kb deletion patients. We contend that the truncated CLN3 protein is unlikely to be expressed in JNCL patients since cellular quality control mechanisms at the RNA and protein levels are likely to degrade the mutant transcript and polypeptides. Moreover, we present analysis identifying the expressed transcripts present in Cln3Δex1-6 mouse brain. From the analysis of expressed Cln3Δex1-6 mouse transcripts, combined with in silico prediction of the expected consequences of the Cln3Δex1-6 mutation on these transcripts, we argue that aberrant Cln3 proteins are unlikely to be expressed in this disease model. Taken together our results indicate that the most common mutation associated with JNCL results in a loss of functional CLN3, that the Cln3Δex1-6 mouse harbors a null Cln3 allele, and that it therefore represents a valid model for this disease.

Climate change and the microbiology of the Antarctic Peninsula region.

Abstract: Antarctic terrestrial ecosystems are cold, dry, low nutrient environments, with large temperature fluctuations and paradoxically low levels of water availability. These extreme environments are dominated by microorganisms (viruses, archaea, eubacteria, fungi and microsporidia, alveolata, stmramenopila, rhodophyta, green algae and protists), which can either tolerate or are adapted to exploit unfavourable growth conditions. However, climate change is altering the growth environment in Antarctica, and so selection pressures on these microorganisms are changing which, in turn, might affect microbial activity in key processes such as biogeochemical cycling. Although the direct effect of a change in, for example, temperature, is known for very few Antarctic microorganisms, molecular techniques (to monitor population structure) and genomic techniques (to identify specific gene function) are starting to give us an insight into what the potential effects of climate change might be at the cellular level. The key to how microorganisms respond to such change depends upon the rate and magnitude of the change along with the physiological capability of microorganisms to adapt or tolerate those changes. Here we will examine a number of case studies in which the effects of factors such as temperature, nutrient availability, grazing, salinity, seasonal cycle and carbon dioxide concentration have each been demonstrated to affect bacterial community structure in polar and alpine ecosystems. The results suggest that the spatial distribution of genetic variation and, hence, comparative rates of evolution, colonization and extinction are particularly important when considering the response of microbial communities to climate change.

Activity of the p110-α subunit of phosphatidylinositol-3-kinase is required for activation of epithelial sodium transport

Abstract: The pathways implicated in the control of epithelial Na+ channel (ENaC)-dependent Na+ transport in renal collecting duct cells share substantial parallels with those implicated in insulin-regulated...

Analysis of NCL Proteins from an Evolutionary Standpoint.

Abstract: The Neuronal Ceroid Lipofuscinoses (NCLs) are the most common group of neurodegenerative disorders of childhood. While mutations in eight different genes have been shown to be responsible for these clinically distinct types of NCL, the NCLs share many clinical and pathological similarities. We have conducted an exhaustive Basic Local Alignment Search Tool (BLAST) analysis of the human protein sequences for each of the eight known NCL proteins- CLN1, CLN2, CLN3, CLN5, CLN6, CLN7, CLN8 and CLN10. The number of homologous species per CLN-protein identified by BLAST searches varies depending on the parameters set for the BLAST search. For example, a lower threshold is able to pull up more homologous sequences whereas a higher threshold decreases this number. Nevertheless, the clade confines are consistent despite this variation in BLAST searching parameters. Further phylogenetic analyses on the appearance of NCL proteins through evolution reveals a different time line for the appearance of the CLN-proteins. Moreover, divergence of each protein shows a different pattern, providing important clues on the evolving role of these proteins. We present and review in-depth bioinformatic analysis of the NCL proteins and classify the CLN-proteins into families based on their structures and evolutionary relationships, respectively. Based on these analyses, we have grouped the CLN-proteins into common clades indicating a common evolving pathway within the evolutionary tree of life. CLN2 is grouped in Eubacteria, CLN1 and CLN10 in Viridiplantae, CLN3 in Fungi/ Metazoa, CLN7 in Bilateria and CLN5, CLN6 and CLN8 in Euteleostomi.

Microbial biodiversity and biogeography

Abstract: This chapter summarizes the major groups of microorganisms found in high latitude aquatic ecosystems and the methodological approaches used to study their biodiversity. The underlying mechanisms that influence microbial biodiversity, including both the survival and dispersal of microorganisms in polar aquatic environments, are explored. The chapter considers the biogeography of microorganisms (i.e., the distribution of taxa) in polar aquatic ecosystems and presents studies that reveal a degree of endemism. To date, studies have shown that among the microorganisms of polar aquatic habitats, morphological class hides a much greater genetic diversity; the extent of the biodiversity uncovered is proportional to sample effort; the vast majority of biodiversity is as yet uncultivated; cosmopolitan groups are present; and that the key environmental factors controlling microbial distribution are temperature and biotic interactions.

Biodiversity of the bacterioplankton in the surface waters around Southern Thule in the Southern Ocean

Abstract: Seven independent clone libraries were constructed to study the biodiversity of the bacterioplankton in the surface waters around Southern Thule, South Sandwich Islands, in order to identify the species present, to determine the sample effort required to estimate the total diversity, and to determine whether the surface waters around Southern Thule represented a highly specialized local anomaly or a subset of the marine meta-community In total, 672 clones generated 629 useable sequences These 629 clones matched 278 different sequences deposited in the 16S rDNA sequence databases The majority of the clones were related to marine microorganisms, many of which had been previously detected in permanently cold Arctic and Antarctic marine environments Each clone library generated an average of 358 new sequence matches 346 clones covered two-thirds of the total estimated diversity, while 438 clones covered three-quarters of the total estimated diversity Above this number, the coverage tended to stabilize and a relatively large number of additional clones were required to improve coverage significantly, increasing at the rate of about one new sequence match per 100 new clones Comparing the different clone libraries, eight matches occurred in each of the seven libraries, whilst fifty-five occurred in only one, suggesting that there might be a relatively small number of common dominant ubiquitous species, with a much larger underlying diversity or ‘seed bank’ from which this dominant diversity is drawn This study suggests that the dominant bacterioplankton in the surface waters around Southern Thule represent a subset of the marine meta-community, whilst sub-dominant diversity appears to be a highly specialized local anomaly