Protein Aggregation in Neurodegeneration

Abstract

Abstract Proteins are essential biomolecules of living cells and organisms. A crucial step during the protein lifecycle is folding, that is, the acquisition of a stable 3D structure by the newly synthesised protein, thanks to which it can perform its biological function. If folding is impaired, misfolded or unfolded proteins can be produced, thus losing their functional properties, being unstable and tending to form aggregates of various entities, which are toxic to cells. In the central nervous system (CNS), the accumulation of misfolded proteins alters the functionality of neurons, leading to the onset of neurodegenerative diseases (NDs), such as Alzheimer disease, Parkinson disease, frontotemporal dementia, amyotrophic lateral sclerosis and Huntington disease. Therapeutic interventions targeting misfolded proteins in NDs are approaching clinical use. However, the complex and overlapping nature of NDs will require a deeper understanding of the underpinning pathological networks. Key Concepts Proteostasis represents an incessant process by which the proteins are maintained in a biologically active state. Protein folding is the regulated process by which a protein assumes a 3D structure that determines a peculiar biological function. Protein folding impairment is called protein misfolding and leads to protein aggregation. Oligomeric assemblies, mature fibrillar aggregates and plaques of misfolded proteins trigger the onset of neurodegeneration. Neurodegeneration is a pathological condition of the nervous system whereby neurons, the main cells involved in memory, cognitive, motor, sensory and behavioural functions inexorably die. Overlapped molecular pathology features translate into similar clinical manifestations in neurodegenerative diseases, whose diagnosis and treatment are challenging.