Iwanir S et al. (2019) Nat Commun "Addendum: Irrational behavior in C. elegans arises from asymmetric modulatory effects within single sensory neurons."

Itskovits E, Ruach R, Bokman E, Iwanir S, Pritz CO, Zaslaver A

[Nat Commun, 2019]

We would like to make our readers aware of the publication by Cohen et al., which reports irrational behaviour in C. elegans olfactory preference[1] . These complementary studies establish C. elegans as a model system to explore the neural mechanisms of decision making.

Cohen, Sarah M et al. (2021) MicroPubl Biol

Sternberg, Paul W, Le, Henry H, Cohen, Sarah M

[MicroPubl Biol, 2021]

The efficient CRISPR/Cas9 genome editing toolkit in the nematode Caenorhabditis elegans has made the creation of null mutants easier than ever. The putative lipid hydrolase lips-6 is known to function in the DAF-12/DIN-1 pathway to promote fat mobilization during periods of starvation in adult worms (Tao et al. 2016). Similarly, it was found to be strongly downregulated in response to dauer ascarosides given during the L1 to L2d decision in larval worms (Cohen et al. 2021). Here, we have created a mutant of the putative lipase lips-6 and studied its lifespan as well as its ascaroside profile.

Moll L et al. (2016) FASEB J "The inhibition of IGF-1 signaling promotes proteostasis by enhancing protein aggregation and deposition."

Reuveni H, Ben-Gedalya T, Moll L, Cohen E

[FASEB J, 2016]

The discovery that the alteration of aging by reducing the activity of the insulin/IGF-1 signaling (IIS) cascade protects nematodes and mice from neurodegeneration-linked, toxic protein aggregation (proteotoxicity) raises the prospect that IIS inhibitors bear therapeutic potential to counter neurodegenerative diseases. Recently, we reported that NT219, a highly efficient IGF-1 signaling inhibitor, protects model worms from the aggregation of amyloid peptide and polyglutamine peptides that are linked to the manifestation of Alzheimer's and Huntington's diseases, respectively. Here, we employed cultured cell systems to investigate whether NT219 promotes protein homeostasis (proteostasis) in mammalian cells and to explore its underlying mechanisms. We found that NT219 enhances the aggregation of misfolded prion protein and promotes its deposition in quality control compartments known as "aggresomes." NT219 also elevates the levels of certain molecular chaperones but, surprisingly, reduces proteasome activity and impairs autophagy. Our findings show that IGF-1 signaling inhibitors in general and NT219 in particular can promote proteostasis in mammalian cells by hyperaggregating hazardous proteins, thereby bearing the potential to postpone the onset and slow the progression of neurodegenerative illnesses in the elderly.-Moll, L., Ben-Gedalya, T., Reuveni, H., Cohen, E. The inhibition of IGF-1 signaling promotes proteostasis by enhancing protein aggregation and deposition.

Dostal V et al. (2010) J Vis Exp "Assaying -amyloid toxicity using a transgenic C. elegans model."

Dostal V, Link CD

[J Vis Exp, 2010]

Accumulation of the -amyloid peptide (A) is generally believed to be central to the induction of Alzheimer's disease, but the relevant mechanism(s) of toxicity are still unclear. A is also deposited intramuscularly in Inclusion Body Myositis, a severe human myopathy. The intensely studied nematode worm Caenorhabditis elegans can be transgenically engineered to express human A. Depending on the tissue or timing of A expression, transgenic worms can have readily measurable phenotypes that serve as a read-out of A toxicity. For example, transgenic worms with pan-neuronal A expression have defects is associative learning (Dosanjh et al. 2009), while transgenic worms with constitutive muscle-specific expression show a progressive, age-dependent paralysis phenotype (Link, 1995; Cohen et al. 2006). One particularly useful C. elegans model employs a temperature-sensitive mutation in the mRNA surveillance system to engineer temperature-inducible muscle expression of an A transgene, resulting in a reproducible paralysis phenotype upon temperature upshift (Link et al. 2003). Treatments that counter A toxicity in this model [e.g., expression of a protective transgene (Hassan et al. 2009) or exposure to Ginkgo biloba extracts (Wu et al. 2006)] reproducibly alter the rate of paralysis induced by temperature upshift of these transgenic worms. Here we describe our protocol for measuring the rate of paralysis in this transgenic C. elegans model, with particular attention to experimental variables that can influence this measurement.