(2022) Development "The people behind the papers - Madeline Cassani and Geraldine Seydoux."

[Development, 2022]

Specification of germ cell fate depends on the asymmetric segregation of germ granules in early embryos. Now, a new paper in Development describes 'germline P-bodies', germ granules in Caenorhabditis elegans embryos, which function cooperatively with another condensate, P granules, in germline specification. To find out more, we caught up with first author Madeline Cassani and corresponding author Geraldine Seydoux, Professor at Johns Hopkins University School of Medicine.

Lins, Jeremy et al. (2022) MicroPubl Biol

Hart, Anne C., Brock, Trisha, Hopkins, Christopher E., Lins, Jeremy

[MicroPubl Biol, 2022]

To study important genes involved in Frontotemporal Dementia ( MAPT , GRN and C9orf72 ), we created deletion alleles in the three orthologous genes ( ptl-1 , pgrn-1 , and alfa-1 ). Simultaneously, we replaced the C. elegans ptl-1 gene with the predicted orthologous human MAPT gene, often called whole-gene humanization, which allows direct assessment of conserved gene function, as well as the opportunity to examine consequences of clinical disease-associated patient variations. Each gene was manipulated using a different selection strategy, including a novel strategy using an unc-18 mutation rescue technique. Clinical MAPT ALS/FTD missense variants G272V and P301L were successfully inserted in hMAPT . Neither ptl-1 loss or clinical variants caused neuronal defects in young adult or aged C. elegans , based on examination of glutamatergic phasmid neurons. Yet, we noted decreased survival to day 9 in the P301L hMAPT strain, compared to control strains. Based on these results, we comment on strategies for humanization, including the importance of confirming C. elegans gene predictions and identifying loss of function defects for each gene before embarking on humanization, and we report the creation of strains and a new gene-editing selection strategy that will be useful for future studies.

Gloeckner C et al. (2010) Proc Natl Acad Sci U S A "Repositioning of an existing drug for the neglected tropical disease Onchocerciasis."

Mersha F, Eubanks LM, Garner AL, Kaufmann GF, Janda KD, Gloeckner C, Lustigman S, Tricoche N, Oksov Y

[Proc Natl Acad Sci U S A, 2010]

Onchocerciasis, or river blindness, is a neglected tropical disease caused by the filarial nematode Onchocerca volvulus that affects more than 37 million people, mainly in third world countries. Currently, the only approved drug available for mass treatment is ivermectin, however, drug resistance is beginning to emerge, thus, new therapeutic targets and agents are desperately needed to treat and cure this devastating disease. Chitin metabolism plays a central role in invertebrate biology due to the critical structural function of chitin for the organism. Taken together with its absence in mammals, targeting chitin is an appealing therapeutic avenue. Importantly, the chitinase OvCHT1 from O. volvulus was recently discovered, however, its exact role in the worm's metabolism remains unknown. A screening effort against OvCHT1 was conducted using the Johns Hopkins Clinical Compound Library that contains over 1,500 existing drugs. Closantel, a veterinary anthelmintic with known proton ionophore activities, was identified as a potent and specific inhibitor of filarial chitinases, an activity not previously reported for this compound. Notably, closantel was found also to completely inhibit molting of O. volvulus infective L3 stage larvae. Closantel appears to target two important biochemical processes essential to filarial parasites. To begin to unravel closantel's effects, a retro-fragment-based study was used to define structural elements critical for closantel's chitinase inhibitor function. As resources towards the development of new agents that target neglected tropical diseases are scant, the finding of an existing drug with impact against O. volvulus provides promise in the hunt for new therapies against river blindness.