Davis, R.E., Wang, J., Kang, Y., Gao, S., Neff, A., Zagoskin, M.
[
International Worm Meeting,
2017]
Maintenance of genome integrity is essential. In the parasitic nematode Ascaris, programmed DNA elimination removes specific DNA sequences from the genome during early development in somatic cells (4-16 cell stage), leaving the germline genome intact. We found that ~13% of the genome is eliminated during DNA elimination. The eliminated DNA consists of repetitive and unique sequences, including ~1000 genes (5% of all genes). The same DNA is eliminated independently in five different pre-somatic cells that give rise to different cell lineages. The eliminated genes are primarily expressed in the germline, suggesting that DNA elimination in Ascaris is an irreversible mechanism for silencing a subset of germline-expressed genes in somatic tissues. We identified ~40 sites where chromosome breaks occur and are healed by telomere addition. We sequenced the genomes of a related horse parasitic nematode Parascaris, that also undergoes DNA elimination, to determine how conserved DNA elimination is in nematodes. The DNA breaks, eliminated genes, and the expression pattern of the eliminated genes are largely conserved between Ascaris and Parascaris indicating that DNA elimination is a specific, conserved and highly regulated process. We further show that Ascaris has holocentric chromosomes in the germline. Prior to DNA elimination in the four-cell embryo, CENP-A, the epigenetic mark of centromeres, is signi?cantly diminished in chromosome regions that will be lost. This leads to the absence of kinetochores and microtubule attachment sites necessary for chromosome segregation, resulting in loss of these chromosome regions during mitosis. These data suggest that CENP-A localization contributes to the identi?cation of regions to be retained and lost playing a regulatory and mechanistic role in DNA elimination. Finally, we identified two worm specific Argonautes (WAGO) associated with condensed chromosomes during DNA elimination. One WAGO preferentially associates with retained DNA only during a DNA elimination mitosis. The other WAGO is enriched on DNA that will be eliminated. Thus, these WAGOs, their associated small RNAs and/or proteins may play a role in nematode DNA elimination. Supported by NIH Grants AI049558 and AI114054 to RED.
Pennington PR, Heistad RM, Nyarko JNK, Barnes JR, Bolanos MAC, Parsons MP, Knudsen KJ, De Carvalho CE, Leary SC, Mousseau DD, Buttigieg J, Maley JM, Quartey MO
[
Sci Rep,
2021]
The pool of -Amyloid (A) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for A peptides. We examined how a naturally occurring variant, e.g. A(1-38), interacts with the AD-related variant, A(1-42), and the predominant physiological variant, A(1-40). Atomic force microscopy, Thioflavin T fluorescence, circular dichroism, dynamic light scattering, and surface plasmon resonance reveal that A(1-38) interacts differently with A(1-40) and A(1-42) and, in general, A(1-38) interferes with the conversion of A(1-42) to a -sheet-rich aggregate. Functionally, A(1-38) reverses the negative impact of A(1-42) on long-term potentiation in acute hippocampal slices and on membrane conductance in primary neurons, and mitigates an A(1-42) phenotype in Caenorhabditis elegans. A(1-38) also reverses any loss of MTT conversion induced by A(1-40) and A(1-42) in HT-22 hippocampal neurons and APOE 4-positive human fibroblasts, although the combination of A(1-38) and A(1-42) inhibits MTT conversion in APOE 4-negative fibroblasts. A greater ratio of soluble A(1-42)/A(1-38) [and A(1-42)/A(1-40)] in autopsied brain extracts correlates with an earlier age-at-death in males (but not females) with a diagnosis of AD. These results suggest that A(1-38) is capable of physically counteracting, potentially in a sex-dependent manner, the neuropathological effects of the AD-relevant A(1-42).
[
Front Pharmacol,
2020]
Oligomeric assembly of Amyloid- (A) is the main toxic species that contribute to early cognitive impairment in Alzheimer's patients. Therefore, drugs that reduce the formation of A oligomers could halt the disease progression. In this study, by using transgenic <i>Caenorhabditis elegans</i> model of Alzheimer's disease, we investigated the effects of frondoside A, a well-known sea cucumber <i>Cucumaria frondosa</i> saponin with anti-cancer activity, on A aggregation and proteotoxicity. The results showed that frondoside A at a low concentration of 1 M significantly delayed the worm paralysis caused by A aggregation as compared with control group. In addition, the number of A plaque deposits in transgenic worm tissues was significantly decreased. Frondoside A was more effective in these activities than ginsenoside-Rg3, a comparable ginseng saponin. Immunoblot analysis revealed that the level of small oligomers as well as various high molecular weights of A species in the transgenic <i>C. elegans</i> were significantly reduced upon treatment with frondoside A, whereas the level of A monomers was not altered. This suggested that frondoside A may primarily reduce the level of small oligomeric forms, the most toxic species of A. Frondoside A also protected the worms from oxidative stress and rescued chemotaxis dysfunction in a transgenic strain whose neurons express A. Taken together, these data suggested that low dose of frondoside A could protect against A-induced toxicity by primarily suppressing the formation of A oligomers. Thus, the molecular mechanism of how frondoside A exerts its anti-A aggregation should be studied and elucidated in the future.