C9ORF72 Regulates Stress Granule Formation and Its Deficiency Impairs Stress Granule Assembly, Hypersensitizing Cells to Stress

Hexanucleotide repeat expansions in the C9ORF72 gene are causally associated with frontotemporal lobar dementia (FTLD) and/or amyotrophic lateral sclerosis (ALS). The physiological function of the normal C9ORF72 protein remains unclear. In this study, we characterized the subcellular localization of C9ORF72 to processing bodies (P-bodies) and its recruitment to stress granules (SGs) upon stress-related stimuli. Gain of function and loss of function experiments revealed that the long isoform of C9ORF72 protein regulates SG assembly. CRISPR/Cas9-mediated knockdown of C9ORF72 completely abolished SG formation, negatively impacted the expression of SG-associated proteins such as TIA-1 and HuR, and accelerated cell death. Loss of C9ORF72 expression further compromised cellular recovery responses after the removal of stress. Additionally, mimicking the pathogenic condition via the expression of hexanucleotide expansion upstream of C9ORF72 impaired the expression of the C9ORF72 protein, caused an abnormal accumulation of RNA foci, and led to the spontaneous formation of SGs. Our study identifies a novel function for normal C9ORF72 in SG assembly and sheds light into how the mutant expansions might impair SG formation and cellular-stress-related adaptive responses.

Tropically-driven climate shifts in southwestern Europe during MIS 19, a low eccentricity interglacial

The relative roles of high- versus low-latitude forcing of millennial-scale climate variability are still not well understood. Here we present terrestrial–marine climate profiles from the southwestern Iberian margin, a region particularly affected by precession, that show millennial climate oscillations related to a nonlinear response to the Earth's precession cycle during Marine Isotope Stage (MIS) 19. MIS 19 has been considered the best analogue to our present interglacial from an astronomical point of view due to the reduced eccentricity centred at 785 ka. In our records, seven millennial-scale forest contractions punctuated MIS 19 superimposed to two orbitally-driven Mediterranean forest expansions. In contrast to our present interglacial, we evidence for the first time low latitude-driven 5000-yr cycles of drying and cooling in the western Mediterranean region, along with warmth in the subtropical gyre related to the fourth harmonic of precession. These cycles indicate repeated intensification of North Atlantic meridional moisture transport that along with decrease in boreal summer insolation triggered ice growth and may have contributed to the glacial inception, at ∼774 ka. The freshwater fluxes during MIS 19ab amplified the cooling events in the North Atlantic promoting further cooling and leading to MIS 18 glaciation. The discrepancy between the dominant cyclicity observed during MIS 1, 2500-yr, and that of MIS 19, 5000-yr, challenges the similar duration of the Holocene and MIS 19c interglacials under natural boundary conditions.

Klima und Landschaftsumgestaltung – Palynologische Hinweise zur Komplexität prähistorischer Mensch-Umwelt-Beziehungen

Pollen analytical studies of four radiocarbon dated sediment records from Switzerland suggest distinct phases of forest clearances and intensified land use from 1450–1250 BC, 650–450 BC, 50 BC–100 AD, and around 700 AD. These land use expansions coincided with periods of warm climate as recorded by Alpine dendroclimatic and Greenland oxygen isotope records. Our results suggest that harvest yields increased synchronously over wide areas of central and southern Europe during periods of warm and dry climate. Positive long-term trends in pollen values of Cerealia and Plantago lanceolata indicate that technical innovations during the Bronze and Iron Ages (e.g. metal ploughs, scythes, hay production, fertilizing methods) gradually increased agricultural productivity. However, our data imply that human societies were not able to compensate rapidly for harvest failures when the climate deteriorated. Agriculture in marginal areas was abandoned, and spontaneous reforestations took place on unoccupied land both north and south of the Alps.