Modulation of caveolae by insulin/IGF-1 signaling regulates aging of Caenorhabditis elegans.

Reducing insulin/IGF-1 signaling (IIS) extends lifespan, promotes protein homeostasis (proteostasis), and elevates stress resistance of worms, flies, and mammals. How these functions are orchestrated across the organism is only partially understood. Here, we report that in the nematode Caenorhabditis elegans, the IIS positively regulates the expression of caveolin-1 (cav-1), a gene which is primarily expressed in neurons of the adult worm and underlies the formation of caveolae, a subtype of lipid microdomains that serve as platforms for signaling complexes. Accordingly, IIS reduction lowers cav-1 expression and lessens the quantity of neuronal caveolae. Reduced cav-1 expression extends lifespan and mitigates toxic protein aggregation by modulating the expression of aging-regulating and signaling-promoting genes. Our findings define caveolae as aging-governing signaling centers and underscore the potential for cav-1 as a novel therapeutic target for the promotion of healthy aging.

Vesicle-mediated secretion of misfolded prion protein molecules from cyclosporin A-treated cells.

Loss of protein homeostasis is a hazardous situation that jeopardizes cellular functionality and viability. Cells have developed mechanisms that supervise protein integrity and direct misfolded molecules for degradation. Nevertheless, subsets of aggregation-prone proteins escape degradation and form aggregates that can underlie the development of neurodegenerative disorders. In some cases, cells deposit hazardous protein aggregates in designated sites, like aggresomes, or secrete them with vesicles. The prion protein (PrP) is an aggregation-prone, membrane-anchored glycoprotein, whose aggregation causes familial and sporadic, fatal, neurodegenerative diseases. The proper maturation of PrP is assisted by cyclophilin B, an endoplasmic reticulum-resident foldase. Accordingly, the inhibition of cyclophilins by the drug cyclosporin A (CsA) leads to the accumulation of aggregated PrP and to its deposition in aggresomes. In this study, we asked whether secretion is an alternative strategy that cells adopt to get rid of misfolded PrP molecules and found that, upon treatment with CsA, cells secrete PrP by exosomes, a subtype of secretion vesicles, and by additional types of vesicles. CsA-induced, PrP-containing exosomes originate from the endoplasmic reticulum in a Golgi-independent manner. These findings divulge a new cellular response that is activated upon CsA treatment to secrete misfolded PrP species from the cell and may underlie the spreading of toxic prions among cells and across tissues.-Pan, I., Roitenberg, N., Cohen, E. Vesicle-mediated secretion of misfolded prion protein molecules from cyclosporin A-treated cells.

A short peptide protects from age-onset proteotoxicity.

Aberrant protein aggregation jeopardizes cellular functionality and underlies the development of a myriad of late-onset maladies including Alzheimer's disease (AD) and Huntington's disease (HD). Accordingly, molecules that mitigate the toxicity of hazardous protein aggregates are of great interest as potential future therapeutics. Here we asked whether a small peptide, composed of five amino acids (5MER peptide) that was derived from the human pro-inflammatory CD44 protein, could protect model nematodes from the toxicity of aggregative proteins that underlie the development of neurodegenerative disorders in humans. We found that the 5MER peptide mitigates the toxicity that stems from both; the AD-causing Aß peptide and a stretch of poly-glutamine that is accountable for the development of several disorders including HD, while minimally affecting lifespan. This protection was dependent on the activity of aging-regulating transcription factors and associated with enhanced Aß and polyQ35-YFP aggregation. A transcriptomic analysis unveiled that the peptide modifies signaling pathways, thereby modulating the expression of various genes, including these, which are known as protein homeostasis (proteostasis) regulators such as txt-13 and modifiers of proteasome activity. The knockdown of txt-13 protects worms from proteotoxicity to the same extent as the 5MER peptide, suggesting that the peptide activates the transcellular chaperone signaling to promote proteostasis. Together, our results propose that the 5MER peptide should be considered as a component of future therapeutic cocktails for the treatment of neurodegenerative maladies.

Neuropeptide signaling and SKN-1 orchestrate differential responses of the proteostasis network to dissimilar proteotoxic insults.

The protein homeostasis (proteostasis) network (PN) encompasses mechanisms that maintain proteome integrity by controlling various biological functions. Loss of proteostasis leads to toxic protein aggregation (proteotoxicity), which underlies the manifestation of neurodegeneration. How the PN responds to dissimilar proteotoxic challenges and how these responses are regulated at the organismal level are largely unknown. Here, we report that, while torsin chaperones protect from the toxicity of neurodegeneration-causing polyglutamine stretches, they exacerbate the toxicity of the Alzheimer's disease-causing Aß peptide in neurons and muscles. These opposing effects are accompanied by differential modulations of gene expression, including that of three neuropeptides that are involved in tailoring the organismal response to dissimilar proteotoxic insults. This mechanism is regulated by insulin/IGF signaling and the transcription factor SKN-1/NRF. Our work delineates a mechanism by which the PN orchestrates differential responses to dissimilar proteotoxic challenges and points at potential targets for therapeutic interventions.

Lipid Assemblies at the Crossroads of Aging, Proteostasis, and Neurodegeneration.

The proteostasis network (PN) is a nexus of mechanisms that act in concert to maintain the integrity of the proteome. Efficiency of the PN declines with age, resulting in the accumulation of misfolded proteins, and in some cases in the development of neurodegenerative disorders. Thus, maintaining an active and efficient PN through the late stages of life could delay or prevent neurodegeneration. Indeed, altering the activity of aging-regulating pathways protects model organisms from neurodegeneration-linked toxic protein aggregation. Here, we delineate evidence that the formation and integrity of lipid assemblies are affected by aging-regulating pathways, and describe the roles of these structures in proteostasis maintenance. We also highlight future research directions and discuss the possibility that compounds which modulate lipid assemblies could be used for the treatment of neurodegenerative disorders.

Expanded CUG Repeats Trigger Disease Phenotype and Expression Changes through the RNAi Machinery in C. elegans.

Myotonic dystrophy type 1 is an autosomal-dominant inherited disorder caused by the expansion of CTG repeats in the 3' untranslated region of the DMPK gene. The RNAs bearing these expanded repeats have a range of toxic effects. Here we provide evidence from a Caenorhabditis elegans myotonic dystrophy type 1 model that the RNA interference (RNAi) machinery plays a key role in causing RNA toxicity and disease phenotypes. We show that the expanded repeats systematically affect a range of endogenous genes bearing short non-pathogenic repeats and that this mechanism is dependent on the small RNA pathway. Conversely, by perturbating the RNA interference machinery, we reversed the RNA toxicity effect and reduced the disease pathogenesis. Our results unveil a role for RNA repeats as templates (based on sequence homology) for moderate but constant gene silencing. Such a silencing effect affects the cell steady state over time, with diverse impacts depending on tissue, developmental stage, and the type of repeat. Importantly, such a mechanism may be common among repeats and similar in human cells with different expanded repeat diseases.

The insulin/IGF signaling cascade modulates SUMOylation to regulate aging and proteostasis in Caenorhabditis elegans.

Although aging-regulating pathways were discovered a few decades ago, it is not entirely clear how their activities are orchestrated, to govern lifespan and proteostasis at the organismal level. Here, we utilized the nematode Caenorhabditis elegans to examine whether the alteration of aging, by reducing the activity of the Insulin/IGF signaling (IIS) cascade, affects protein SUMOylation. We found that IIS activity promotes the SUMOylation of the germline protein, CAR-1, thereby shortening lifespan and impairing proteostasis. In contrast, the expression of mutated CAR-1, that cannot be SUMOylated at residue 185, extends lifespan and enhances proteostasis. A mechanistic analysis indicated that CAR-1 mediates its aging-altering functions, at least partially, through the notch-like receptor glp-1. Our findings unveil a novel regulatory axis in which SUMOylation is utilized to integrate the aging-controlling functions of the IIS and of the germline and provide new insights into the roles of SUMOylation in the regulation of organismal aging.