Research Topic

The Role of the Protein Quality Control in Neurodegenerative Diseases

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Several types of neurodegenerative diseases are associated to the presence of protein inclusions formed by the accumulation of aggregating misfolded proteins. The aggregation process is indicative of an insufficient protection exerted by the protein quality control (PQC) system in neuronal cells and other ...

Several types of neurodegenerative diseases are associated to the presence of protein inclusions formed by the accumulation of aggregating misfolded proteins. The aggregation process is indicative of an insufficient protection exerted by the protein quality control (PQC) system in neuronal cells and other cell types targeted by proteotoxic stresses before onset or during progression of disease.

The PQC system is composed of a complex network of interconnected factors that work together to counteract the chance of newly synthetized proteins to undergo unfolding/misfolding and to avoid that damaged and/or misfolded proteins will escape the intracellular clearance pathways, thereby ensuring the maintenance of protein homeostasis. The activity of the PQC system begins at the translational levels, at the polyribosomes; here, translation stalling avoids the synthesis of defective ribosomal products that would undergo misfolding and may exert toxic functions. Upon proteotoxic stress conditions, the attenuation of translation rate and the sequestration of mRNAs encoding for housekeeping proteins into stress granules allows the redirection the energies towards essential pro-survival pathways and it avoids the production of newly synthetized proteins that, due to the ongoing stress, might undergo unfolding/misfolding.

Subsequently, during post-translational modification chaperones located in the cytoplasm, endoplasmic reticulum and even in the mitochondria assure proper protein folding. If they fail, proteins are directed by chaperones to selective degradation that may include the unfolded protein response (UPS), the cytoplasmic and nuclear ubiquitin proteasome system (UPS) or the cytoplasmic autophagic process (macro-, micro or chaperone mediated- autophagies).

The failure of the PQC system is often associated to neurodegenerative processes and depends on several factors that include aging, gene variability that results in misregulation of specific PQC components, excessive production of misfolded proteins as a consequence of gene mutations, etc. Therefore, the potentiation of the PQC system response in neurodegenerative diseases is though to be a valuable approach that could be beneficial to counteract disease progression, ameliorating quality of life and extending the survival of affected patients.

In this Topic all different aspects the of PQC system will be deeply discussed along with the various approaches attempted to enhance its activity with genetic and pharmacological approaches aimed to find treatment to combat neurodegenerative diseases.


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