α-Synuclein: An All-Inclusive Trip Around its Structure, Influencing Factors and Applied Techniques

Abstract

Alpha-synuclein (αSyn) is a highly expressed and conserved protein, typically found in the presynaptic terminals of neurons. The misfolding and aggregation of αSyn into amyloid fibrils is a pathogenic hallmark of several neurodegenerative diseases called synucleinopathies, such as Parkinson’s disease. Since αSyn is an Intrinsically Disordered Protein, the characterization of its structure remains very challenging. Moreover, the mechanisms by which the structural conversion of monomeric αSyn into oligomers and finally into fibrils takes place is still far to be completely understood. Over the years, various studies have provided insights into the possible pathways that αSyn could follow to misfold and acquire oligomeric and fibrillar forms. In addition, it has been observed that αSyn structure can be influenced by different parameters, such as mutations in its sequence, the biological environment (e.g., lipids, endogenous small molecules and proteins), the interaction with exogenous compounds (e.g., drugs, diet components, heavy metals). Herein, we review the structural features of αSyn (wild-type and disease-mutated) that have been elucidated up to present by both experimental and computational techniques in different environmental and biological conditions. We believe that this gathering of current knowledge will further facilitate studies on αSyn, helping the planning of future experiments on the interactions of this protein with targeting molecules especially taking into consideration the environmental conditions.

Protein clearance strategies for disease intervention

“…Protein stabilizers can be described as other proteins, peptides or small molecules that bind to a protein and prevent it from unfolding or aggregation. For instance, phthalocyanine tetrasulfonate (PcTs) can interact with the N-terminal region of α-syn, leading to its stabilization through salt bridges and π–π stacking interactions (Bisi et al 2021 ; Lee et al 2004 ). Importantly, PcTs can reduce cell death, fibril formation and amyloidosis induced by wild-type or mutant α-syn (Fonseca-Ornelas et al 2014 ; Lamberto et al 2009 ; Lee et al 2004 ).…”

Plant Polyphenols for Aging Health: Implication from Their Autophagy Modulating Properties in Age-Associated Diseases

“…Neurodegenerative diseases are a range of diseases of the brain, including Parkinson’s disease (PD) and Alzheimer’s disease, which result in neuron damage, brain atrophy, and consequently, the loss of cognitive or physical abilities. Several factors, including oxidative, endoplasmic stress, impairment in protein folding machinery, defects of damaged protein/organelle clearance mechanism, play key roles in the disease pathogenesis [ 241 , 242 , 243 , 244 , 245 , 246 , 247 , 248 ] and targeting these mechanisms alleviates the condition and offers neuroprotection.…”

Lipid level alteration in human and cellular models of alpha synuclein mutations

“…Indeed, α-Syn and cellular lipids entertain bidirectional interactions: the presence of lipid rafts in specific cellular membranes attract α-Syn to these subcellular locations 11 , and in turn, α-Syn can regulate lipid metabolism via its location at the mitochondria associated endoplasmic reticulum (ER) membranes or MAM 11 , transient lipid-raft domain in the ER involved in the regulation of multiple lipid enzymes. Moreover, it was reported that α-Syn aggregation, which is a hallmark of PD pathology, may depend on the concentration of different lipids in cells and lysosomal membranes 12 , 13 . Here, we hypothesized that a-Syn contributes to the regulation of lipid homeostasis via its effect on the modulation of MAM activities and that we will be able to observe these changes in patients’ serum.…”