The Toxicity of Protein Aggregates: New Insights into the Mechanisms

The aberrant aggregation of specific peptides and proteins is the common feature of a range of more than 50 human pathologies, collectively referred to as protein misfolding diseases. Among them, neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases (AD and PD, respectively) represent a real burden in terms of disability and health care cost. Specifically, AD is characterized by the accumulation of aberrant aggregates of the amyloid-β peptide (Aβ) and hyperphosphorylated tau protein, whereas PD is defined by the aggregation and accumulation of α-synuclein (αS). In these conditions, misfolded monomeric proteins undergo conformational shifts, facilitating the aggregation and formation of insoluble amyloid fibrils. Although the presence of inclusions is considered to be a cardinal pathological hallmark, their abundance does not directly correlate with the disease phenotype observed in patients. Accordingly, a robust body of evidence indicates that oligomeric species formed at the early stages of the aggregation process are primarily responsible for neuronal toxicity. Many hypotheses have been proposed to explain the molecular pathogenesis of neurodegeneration, but despite considerable efforts by researchers in recent decades, it has not been completely elucidated and further investigations are still necessary.