PIMT AND SIGNALING

Interaction between the protein repair enzyme L-isoaspartyl methyltransferase and insulin/IGF-1 signaling in mice and worms

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 Obiettivo del progetto (Objective)

'The protein L-isoaspartyl methyltransferase (PIMT) is well known for its protein repair function, namely the reconversion of deamidated and/or isomerized asparaginyl and aspartyl residues (L-isoaspartyl residues) into their normal, non-isomerized forms. The conversion of biomolecules to non-useful and potentially toxic products by unwanted chemical reactions represents probably an important aspect of the aging process in living organisms. To the extent that they can minimize the accumulation of damaged molecules, they can endure. PIMT knockout mice accumulate high levels of damaged proteins in their tissues, especially the brain, and die of massive seizures at an average age of 42 days. On the other hand, worms and flies overexpressing this enzyme live longer, strongly suggesting a role for PIMT in the aging process. A particularly intriguing observation is that the insulin/IGF-1 signaling pathway is activated in the brain of PIMT knockout mice. Genetic evidence also exists for an interaction between PIMT and insulin-like signaling in Caenorhabditis elegans. It has recently become clear that insulin-like signaling plays an important role in the regulation of the aging process. Lowered insulin/IGF-1 signaling, especially in neuronal tissues, leads to lifespan extension in worms, flies and mice. The overall objective of this project is to understand the link between PIMT and insulin-like signaling. A first aim is to consolidate the interaction between PIMT and insulin-like signaling in worms. A second aim is to analyze the effect of PIMT deficiency on the phosphoproteome of mouse brains. A third aim is to elucidate the mechanism by which PIMT deficiency leads to the observed changes in protein phosphorylation. Several routes, including direct regulation of protein phosphatase activity by PIMT methylation, modulation of such an activity by a critical isoaspartyl residue, and effect of high isoaspartyl content in a protein on its phosphorylation state will be explored.'

Introduzione (Teaser)

European scientists have teamed up to investigate the intriguing process of ageing. Using various animal models they hope to recapitulate their findings in humans.

Descrizione progetto (Article)

It is well established that all organisms have a set lifespan. Although to an extent this is genetically determined, there are internal and external factors which influence ageing. Indeed, ageing is a complex process characterised by multi-parameter alterations in the function of physiological cells. An important aspect of ageing in living organisms involves the conversion of biomolecules to non-useful and potentially toxic products.

The protein L-isoaspartyl methyltransferase (PIMT) is well known for its protein repair function. Mice lacking PIMT accumulate high levels of damaged proteins in their tissues, especially in the brain, and die at an average age of 42 days. At the same time, flies and worms overexpressing the protein live longer, clearly underscoring the involvement of PIMT in the ageing process.

Interestingly, the absence of PIMT is inversely associated with insulin/IGF-1 signalling. Scientists on the EU-funded PIMT AND SIGNALING project propose to investigate the interaction between the two pathways and the effect of PIMT on protein phosphorylation.

In this context, researchers have generated C.elegans worms lacking or overexpressing the isoaspartyl methyltransferase protein. So far they have identified one downstream transcriptional effector of the insulin-like signalling pathway called DAF-16.

Ongoing experiments are destined to identify which protein targets are altered during PIMT deficiency and decipher a mechanistic link between PIMT and growth factor signalling. Finally, using zebrafish as a model, scientists hope to explain how PIMT deficiency can lead to epileptic seizures.

The PIMT AND SIGNALING project demonstrates how different model organisms can improve our understanding of the mechanism of action of specific genes and their products. Such organisms could prove to be indispensable tools in the quest for the 'absolute' mechanisms of ageing.