SignificanceMutations in the GRN gene cause frontotemporal dementia, a devastating neurological disease. The majority of these GRN mutations are nonsense and frameshift mutations. Here, we generated a knockin mouse model with a Grn mutation corresponding to the most prevalent human disease mutation, GRNR493X. We show that mice harboring this mutation phenocopy progranulin-deficient mice, and that the mutation triggers mRNA decay and, as a consequence, low production of Grn. However, the truncated mutant protein that would be produced from this allele is functional, suggesting inhibiting mRNA decay as a therapeutic approach for individuals with progranulin-deficient frontotemporal dementia caused by nonsense mutations.

Progranulin is a widely expressed, cysteine-rich, secreted glycoprotein originally discovered for its growth factor–like properties. Its subsequent identification as a causative gene for frontotemporal dementia (FTD), a devastating early-onset neurodegenerative disease, has catalyzed a surge of new discoveries about progranulin’s function in the brain. More recently, progranulin was recognized as an adipokine involved in diet-induced obesity and insulin resistance, revealing its metabolic function. Here, we review progranulin biology in both neurodegenerative and metabolic diseases. In particular, we highlight progranulin’s growth factor–like, trophic, and anti-inflammatory properties as potential unifying themes in these seemingly divergent conditions. We also discuss potential therapeutic options for raising progranulin levels to treat progranulin-deficient FTD, as well as the possible consequences of such treatment.

The neural functions of adropin, a secreted peptide highly expressed in the brain, have not been investigated. In humans, adropin is highly expressed in astrocytes and peaks during critical postnatal periods of brain development. Gene enrichment analysis of transcripts correlating with adropin expression suggests processes relevant to aging-related neurodegenerative diseases that vary with age and dementia state, possibly indicating survivor bias. In people aged <40 y and ‘old-old’ (>75 y) diagnosed with dementia, adropin correlates positively with genes involved in mitochondrial processes. In the ‘old-old’ without dementia adropin expression correlates positively with morphogenesis and synapse function. Potent neurotrophic responses in primary cultured neurons are consistent with adropin supporting the development and function of neural networks. Adropin expression in the ‘old-old’ also correlates positively with protein markers of tau-related neuropathologies and inflammation, particularly in those without dementia. How variation in brain adropin expression affects neurological aging was investigated using old (18-month) C57BL/6J mice. In mice adropin is expressed in neurons, oligodendrocyte progenitor cells, oligodendrocytes, and microglia and shows correlative relationships with groups of genes involved in neurodegeneration and cellular metabolism. Increasing adropin expression using transgenesis improved spatial learning and memory, novel object recognition, resilience to exposure to new environments, and reduced mRNA markers of inflammation in old mice. Treatment with synthetic adropin peptide also reversed age-related declines in cognitive functions and affected expression of genes involved in morphogenesis and cellular metabolism. Collectively, these results establish a link between adropin expression and neural energy metabolism and indicate a potential therapy against neurological aging.

BackgroundThe eusocial Hymenoptera have radiated across a wide range of thermal environments, exposing them to significant physiological stressors. We reconstructed the evolutionary history of three families of Heat Shock Proteins (Hsp90, Hsp70, Hsp40), the primary molecular chaperones protecting against thermal damage, across 12 Hymenopteran species and four other insect orders. We also predicted and tested for thermal inducibility of eight Hsps from the presence of cis-regulatory heat shock elements (HSEs). We tested whether Hsp induction patterns in ants were associated with different thermal environments.ResultsWe found evidence for duplications, losses, and cis-regulatory changes in two of the three gene families. One member of the Hsp90 gene family, hsp83, duplicated basally in the Hymenoptera, with shifts in HSE motifs in the novel copy. Both copies were retained in bees, but ants retained only the novel HSE copy. For Hsp70, Hymenoptera lack the primary heat-inducible orthologue from Drosophila melanogaster and instead induce the cognate form, hsc70-4, which also underwent an early duplication. Episodic diversifying selection was detected along the branch predating the duplication of hsc70-4 and continued along one of the paralogue branches after duplication. Four out of eight Hsp genes were heat-inducible and matched the predictions based on presence of conserved HSEs. For the inducible homologues, the more thermally tolerant species, Pogonomyrmex barbatus, had greater Hsp basal expression and induction in response to heat stress than did the less thermally tolerant species, Aphaenogaster picea. Furthermore, there was no trade-off between basal expression and induction.ConclusionsOur results highlight the unique evolutionary history of Hsps in eusocial Hymenoptera, which has been shaped by gains, losses, and changes in cis-regulation. Ants, and most likely other Hymenoptera, utilize lineage-specific heat inducible Hsps, whose expression patterns are associated with adaptive variation in thermal tolerance between two ant species. Collectively, our analyses suggest that Hsp sequence and expression patterns may reflect the forces of selection acting on thermal tolerance in ants and other social Hymenoptera.Electronic supplementary materialThe online version of this article (doi:10.1186/s12862-015-0573-0) contains supplementary material, which is available to authorized users.

Temperature increases associated with global climate change are likely to be accompanied by additional environmental stressors such as desiccation and food limitation, which may alter how temperature impacts organismal performance. To investigate how interactions between stressors influence thermal tolerance in the common forest ant, Aphaenogaster picea, we compared the thermal resistance of workers to heat shock with and without pre-exposure to desiccation or starvation stress. Knockdown (KD) time at 40.5 °C of desiccated ants was reduced 6% compared to controls, although longer exposure to desiccation did not further reduce thermal tolerance. Starvation, in contrast, had an increasingly severe effect on thermal tolerance: at 21 days, average KD time of starved ants was reduced by 65% compared to controls. To test whether reduction in thermal tolerance results from impairment of the heat-shock response, we measured basal gene expression and transcriptional induction of two heat-shock proteins (hsp70 and hsp40) in treated and control ants. We found no evidence that either stressor impaired the Hsp response: both desiccation and starvation slightly increased basal Hsp expression under severe stress conditions and did not affect the magnitude of induction under heat shock. These results suggest that the co-occurrence of multiple environmental stressors predicted by climate change models may make populations more vulnerable to future warming than is suggested by the results of single-factor heating experiments.

For insect species in temperate environments, seasonal timing is often governed by the regulation of diapause, a complex developmental programme that allows insects to weather unfavourable conditions and synchronize their life cycles with available resources. Diapause development consists of a series of distinct phases including initiation, maintenance, termination and post-diapause development. The evolution of insect seasonal timing depends in part on how these phases of diapause development and post-diapause development interact to affect variation in phenology. Here, we dissect the physiological basis of a recently evolved phenological shift in Rhagoletis pomonella (Diptera: Tephritidae), a model system for ecological divergence. A recently derived population of R. pomonella shifted from specializing on native hawthorn fruit to earlier fruiting introduced apples, resulting in a 3-4 week shift in adult emergence timing. We tracked metabolic rates of individual flies across post-winter development to test which phases of development may act either independently or in combination to contribute to this recently evolved divergence in timing. Apple and hawthorn flies differed in a number of facets of their post-winter developmental trajectories. However, divergent adaptation in adult emergence phenology in these flies was due almost entirely to the end of the pupal diapause maintenance phase, with post-diapause development having a very small effect. The relatively simple underpinnings of variation in adult emergence phenology suggest that further adaptation to seasonal change in these flies for this trait might be largely due to the timing of diapause termination unhindered by strong covariance among different components of post-diapause development.

Background: Progranulin is a secreted, anti-inflammatory glycoprotein, suggested to be a component of high density lipoproteins (HDL). Results: Studies in cells and plasma revealed secreted progranulin exists as a homodimer, does not bind lipids, and is not detected on HDL. Conclusion: Secreted progranulin exists as a homodimer and is not an HDL component. Significance: These data provide insights into the molecular properties of secreted progranulin.

BackgroundThe distributions of species and their responses to climate change are in part determined by their thermal tolerances. However, little is known about how thermal tolerance evolves. To test whether evolutionary extension of thermal limits is accomplished through enhanced cellular stress response (enhanced response), constitutively elevated expression of protective genes (genetic assimilation) or a shift from damage resistance to passive mechanisms of thermal stability (tolerance), we conducted an analysis of the reactionome: the reaction norm for all genes in an organism’s transcriptome measured across an experimental gradient. We characterized thermal reactionomes of two common ant species in the eastern U.S, the northern cool-climate Aphaenogaster picea and the southern warm-climate Aphaenogaster carolinensis, across 12 temperatures that spanned their entire thermal breadth.ResultsWe found that at least 2 % of all genes changed expression with temperature. The majority of upregulation was specific to exposure to low temperatures. The cool-adapted A. picea induced expression of more genes in response to extreme temperatures than did A. carolinensis, consistent with the enhanced response hypothesis. In contrast, under high temperatures the warm-adapted A. carolinensis downregulated many of the genes upregulated in A. picea, and required more extreme temperatures to induce down-regulation in gene expression, consistent with the tolerance hypothesis. We found no evidence for a trade-off between constitutive and inducible gene expression as predicted by the genetic assimilation hypothesis.ConclusionsThese results suggest that increases in upper thermal limits may require an evolutionary shift in response mechanism away from damage repair toward tolerance and prevention.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2466-z) contains supplementary material, which is available to authorized users.