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Summary Amyotrophic Lateral Sclerosis (ALS) is a synaptopathy accompanied by the presence of cytoplasmic aggregates containing TDP-43, an RNA binding protein linked to ~97% of ALS cases. Using a Drosophila model of ALS, we show that TDP-43 OE in motor neurons results in decreased expression of the Hsc70-4 chaperone at the neuromuscular junction (NMJ). Mechanistically, mutant TDP-43 sequesters hsc70-4 mRNA and impairs its translation. Expression of Hsc70-4’s ortholog, HSPA8 is also reduced in primary motor neurons and NMJs of mice expressing mutant TDP-43. Electrophysiology, imaging, and genetic interaction experiments reveal TDP-43 dependent defects in synaptic vesicle endocytosis. These deficits can be partially restored by OE of Hsc70-4, cysteine-string protein (Csp) or dynamin. This suggests that TDP-43 toxicity results in part from impaired activity of the synaptic CSP/Hsc70 chaperone complex impacting dynamin function. Finally, Hsc70-4/HSPA8 expression is also post-transcriptionally reduced in fly and human iPSC C9orf72 models, suggesting a common disease pathomechanism.

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Along a transect of mature forests from Wisconsin to Nova Scotia, hemlock attains dominance most frequently where soil is thin or low in stored nutrients. Very probably, soil is also dependably moistened either by climate or seepage. The inability of shade-tolerant competitors to survive suppression on thin or infertile soil may explain hemlock's success, even though hemlock maintains understory populations at very low densities. Hemlock also grows well on moist uplands with richer soil but does not often attain dominance or form large aggregates in a continuously varying mixed forest. This is in contrast to hemlock's codominance on a wide variety of upland sites in the presettlement forest. Recent history, then, may best explain the rarity of hemlock-dominated stands on richer sites: (1) hemlock is sensitive at all stages of its life cycle to disturbances that were intensified after European settlement as well as to the kinds of animal consumption that increase with disturbance; (2) disturbance has been most frequent on sites with richer soils; and (3) hemlock does not compete well with shade-tolerant trees such as sugar maple, beech, and red spruce that are better adapted to disturbance. These species can increase at the expense of hemlock because they have less rigorous requirements for seedling establishment, are not as palatable to consumers, or, in the case of sugar maple and beech, have deeper root systems and can sucker or sprout after extensive shoot damage.

Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case–control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43–1.96); P=1.1 × 10−10). We finally searched for association between SNPs within the FRMD4A locus and Aβ plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Aβ42/Aβ40 ratio (best signal, P=5.4 × 10−7). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.