Skip to main content

Prenylated protein regulation in the Caenorhabditis elegans brain

Final Report Summary - PPRITCEB (Prenylated protein regulation in the Caenorhabditis elegans brain)

Proteins are nanomachines involved in all biological processes. Therefore, tight regulation of protein localization within cells is essential for cellular function. In cells, proteins are targeted to cellular membrane in several ways, among them, is the addition of a short lipid moiety to the protein tail (prenylation). The prenylated proteins are then escorted to the membrane by a chaperon protein called PrBP. However, many aspects about the way PrBP acts are still not known. Moreover, in many cases, the function of its substrates is elusive. In this grant proposal, we have used the worm C. elegans to explore the function of prenylated proteins in aging. Working with C. elegans provides many advantages including:
(1) Short lifespan and life cycle. The average lifespan of worms is 12-18 days in 20ºC and the generation time is 3-4 days. Therefore, we can easily explore the effect of genes on lifespan.
(2) The worms are hermaphrodites. Therefore, the daughters are identical to their mother and among themselves. This property allow us to determine how a single gene variant effect the physiology of the worm. Moreover, each worms lay about 300 eggs in a few days.
(3) Vast genetic tools. We can easily manipulate the function of genes in C. elegans using methods such as CRISPR/Cas9 and RNA silencing.
(4) The worms is semitransparent. Therefore, we can use microscopy to explore the function of genes in living worms.
(5) The worms is small (~1 mm). Therefore, we can grow hundreds of worms in a single petri dish.

C. elegans expresses one PrBP ortholog, namely PDL-1. PDL-1 escorts the soluble guanylate cyclases (sGCs) GCY-33 and GCY-35 to the dendritic endings of the BAG and URX oxygen sensing neurons, respectively. sGCs are conserved enzymes that catalyze the formation of the second messenger cyclic GMP (cGMP) from GTP. In this way sGCs regulate important and diverse physiological processes including blood pressure, platelet aggregation, and brain activity. Our project reveal that joint loss of function of gcy-35 and the neuropeptide receptor npr-1 results in increased lifespan. The increased lifespan is dependent on GCY-33. Intriguingly, we show that the function of NPR-1 and GCY-35 in lifespan is synergistic. Indeed, deleting just gcy-35 does not increase lifespan, and loss-of-function of npr-1 provides only a small increase. In addition to the lifespan lengthening, the joint inhibition of gcy-35 and npr-1 increases the resistance of worms to ultra violet radiation and to bacterial infection. However, these worms were sensitive to heat and oxidative stress, indicating that the beneficial effect of gcy-35/npr-1 loss-of-function is specific to certain stress conditions. Some long-lived C. elegans mutants have developmental, and metabolic impairments. However, our data show that gcy-35/npr-1 mutants are healthy and maintain high metabolic activity. The insulin and hypoxia signaling pathways are important for lifespan regulation. We show that these pathways are essential for the long lifespan of gcy-35/npr-1 worms. Moreover, we show that reactive oxygen species (ROS) are essential for the extended lifespan. Importantly, for many years ROS were thought to accelerate the aging process. In this respect, our data support previous studies that suggest that non-toxic level of ROS have the opposite effect on lifespan. In conclusion, our studies identified novel regulators of the aging process. For the first time, we show that prenylated sGCs genetically interact with neuropeptide, insulin, and hypoxia signaling pathways, and that these genetic interaction are essential for lifespan regulation. Notably, we recently published some of these results in the Aging Cell journal (Abergel, Livshits et al., 2017). Aging regulation is a fascinating field with vast implications for the society and economy. Moreover, since the occurrence of many diseases (e.g. Alzheimer’s, Parkinson’s, many type of cancer) increases with age, increasing lifespan could be considered as a promising therapy for these maladies. In this respect, our studies may provide important insights about the mechanism underlying aging and thus help the development of anti-aging therapy.

Abergel R, Livshits L, Shaked M, Chatterjee AK, Gross E (2017) Synergism between soluble guanylate cyclase signaling and neuropeptides extends lifespan in the nematode Caenorhabditis elegans. Aging cell 16: 401-413.