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Synaptic stability and modifiability:protein synthesis and degradation in neurons

Final Report Summary - NEURONALPROTEOSTASIS (Synaptic stability and modifiability:protein synthesis and degradation in neurons)

In all cell types, including neurons, the proteome is regulated in a dynamic way to maintain cellular function. In neurons, proteostatic regulation occurs in the cell body as well as in the dendrites and potentially in axons. It is clear that protein synthesis and degradation are responsible for changes in the cell body and synaptic proteome. But is not well understood how these two processes are coordinated to achieve the desired level of individual proteins in neurons.

Compartmentalized neuronal protein synthesis. Classically it was assumed that all the proteins required for neuronal function were synthesized in the neuronal cell body, but in recent years, the idea of local protein synthesis have been demonstrated.
In 1996 the first functional role for local protein synthesis was discovered: local protein synthesis is required for the rapid enhancement of synaptic transmission induced by exposure to the growth factor BDNF. These findings have been furthered by subsequent studies in different model organisms showing that local protein synthesis plays an important role in inducing different forms of plasticity.

The big picture. The published work is consistent with the idea that the protein synthesis and degradation machinery are present in the same subcellular compartment, suggesting that there must exist coordination between these opposing processes to achieve the necessary protein concentration. This cell biological suggestion is supported by functional studies, suggesting a role for both protein synthesis and degradation in neuronal plasticity. Only a handful of studies have begun to look at both processes together.

The overall goal of this proposal is to determine how protein synthesis and degradation are coordinated and how they work together in response to plasticity induction. Because very little is known about this coordination in neurons, initial experiments will include global manipulations of protein synthesis and degradation to determine whether such manipulations elicit opposing or compensatory changes in the other process. Also we want study the interaction of protein synthesis and degradation specifically in dendrites where the cell biological machinery for protein synthesis and degradation is localized.

In this study we focused in the role of the protein degradation by the ubiquitin proteasome pathway, one of the major pathways for protein degradation. The first question we aimed to answer was: if protein degradation is prevented, how does the protein synthesis machinery respond? We found a dramatic decrease in protein synthesis after proteasome inhibition; this decrease in general protein degradation was accompanied by an increase in the synthesis of specific proteins. We examined the nature of this response and which molecules are implicated in the communication between protein synthesis and degradation in neurons. we found a chemical compound that is able to revert the effect of the inhibition of protein synthesis after the proteasome inhibition. This compound acts on one of the identified key modulators of the response confirming the role of this protein in the pathway that coordinates protein synthesis and degradation.
Following these broad manipulations, I am currently examining how the inhibition of protein degradation affects protein synthesis locally in dendrites, with a special emphasis on the extent to which local protein synthesis and degradation, taking place in dendrites, are coordinated.

A deep understanding of how protein synthesis and degradation are coordinated in post mitotic cells such as neurons will help to understand how these cells deal with stress conditions. Furthermore protein degradation has been reported being decreased with age, and proteasome dysfunction is related with some diseases such as Parkinson Disease or Alzheimer disease.