Showing papers by "David A. Pearce published in 2020"

A tailored Cln3 Q352X mouse model for testing therapeutic interventions in CLN3 Batten disease

Abstract: CLN3 Batten disease (CLN3 disease) is a pediatric lysosomal storage disorder that presents with progressive blindness, motor and cognitive decline, seizures, and premature death CLN3 disease results from mutations in CLN3 with the most prevalent mutation, a 966 bp deletion spanning exons 7–8, affecting ~ 75% of patients Mouse models with complete Cln3 deletion or Cln3Δex7/8 mutation have been invaluable for learning about both the basic biology of CLN3 and the underlying pathological changes associated with CLN3 disease These models, however, vary in their disease presentation and are limited in their utility for studying the role of nonsense mediated decay, and as a consequence, in testing nonsense suppression therapies and read-through compounds In order to develop a model containing a disease-causing nonsense point mutation, here we describe a first-of-its-kind Cln3Q352X mouse model containing a c1054C > T (pGln352Ter) point mutation Similar to previously characterized Cln3 mutant mouse lines, this novel model shows pathological deficits throughout the CNS including accumulation of lysosomal storage material and glial activation, and has limited perturbation in behavioral measures Thus, at the molecular and cellular level, this mouse line provides a valuable tool for testing nonsense suppression therapies or read through compounds in CLN3 disease in the future

Functional Associations and Resilience in Microbial Communities.

Abstract: Microbial communities have inherently high levels of metabolic flexibility and functional redundancy, yet the structure of microbial communities can change rapidly with environmental perturbation To understand whether such changes observed at the taxonomic level translate into differences at the functional level, we analyzed the structure of taxonomic and functional gene distribution across Arctic and Antarctic locations Taxonomic diversity (in terms of alpha diversity and species richness) differed significantly with location However, we found that functional genes distributed evenly across bacterial networks and that this functional distribution was also even across different geographic locations For example, on average 15% of the functional genes were related to carbon cycling across all bacterial networks, slightly over 21% of the genes were stress-related and only 05% of the genes were linked to carbon degradation functions In such a distribution, each bacterial network includes all of the functional groups distributed following the same proportions However, the total number of functional genes that is included in each bacterial network differs, with some clusters including many more genes than others We found that the proportion of times a specific gene must occur to be linked to a specific cluster is 8%, meaning the relationship between the total number of genes in the cluster and the number of genes per function follows a linear pattern: smaller clusters require a gene to appear less frequently to get fixed within the cluster, while larger clusters require higher gene frequencies We suggest that this mechanism of functional association between equally rare or equally abundant genes could have implications for ecological resilience, as non-dominant genes also associate in fully functioning ecological networks, potentially suggesting that there are always pre-existing functional networks available to exploit new ecological niches (where they can become dominant) as they emerge; for example, in the case of rapid or sudden environmental change Furthermore, this pattern did not correlate with taxonomic distribution, suggesting that bacteria associate based on functionality and this is independent of its taxonomic position Our analyses based on ecological networks also showed no clear evidence of recent environmental impact on polar marine microbial communities at the functional level, unless all communities analyzed have changed exactly in the same direction and intensity, which is unlikely given we are comparing areas changing at different rates