Role of post-translational modifications in modulating the structure, function and toxicity of α-synuclein

Abstract

A better understanding of the molecular and cellular determinants that influence the pathology of Parkinson's disease (PD) is essential for developing effective diagnostic, preventative and therapeutic strategies to treat this devastating disease. A number of post-translational modifications to a-syn are present within the Lewy bodies in the brains of affected patients and transgenic models of PD and related disorders. However, whether disease-associated a-syn post-translational modifications promote or inhibit a-syn aggregation and neurotoxicity in vivo remains unknown. Herein, we summarize and discuss the major disease-associated post-translational modifications (phosphorylation, truncation and ubiquitination) and present our current understanding of the effect of these modifications on a-syn aggregation and toxicity. Elucidating the molecular mechanisms underlying post-translation modifications of a-syn and the consequences of such modifications on the biochemical, structural, aggregation and toxic properties of the protein is essential for unravelling the molecular basis of its function(s) in health and disease. Furthermore, the identification of the natural enzymes involved in regulating the post-translational modifications of a-synuclein will yield novel and more tractable therapeutic targets to treat PD and related synucleinopathies.

Chaperone-mediated autophagy: roles in disease and aging

“…Perturbation of α-synuclein degradation as a consequence of unfavorable post-translational modifications caused by environmental or cellular stressors (for example, pesticides, oxidative stress, so on) is a key event in the pathogenesis of sporadic PD and various synucleinopathies [57]. Among the different posttranslational modifications described for the α-synuclein proteins that accumulate in inclusions in PD neurons, dopamine-modified α-synuclein has shown reduced susceptibility to CMA degradation in a manner similar to that of familial α-synuclein mutants [51].…”

Nanoscopic Characterisation of Individual Endogenous Protein Aggregates in Human Neuronal Cells

“…Similarly, in PD, aggregates of the protein α‐synuclein (αS) are found in Lewy bodies3 within neuronal cells. These proteins are often heavily post‐translationally modified, for example, αS undergoes phosphorylation, nitration and truncation,4, 5, 6 this makes it important to be able to characterise the real endogenous aggregates formed in cells, as these can differ from those formed by unmodified proteins.…”

One-pot total chemical synthesis of human α-synuclein

“…1 Histologically, PD is defined post-mortem by the presence of intracellular proteinaceous inclusions known as Lewy bodies (LBs), composed mainly of insoluble a-syn amyloid fibrils. Several post-translational modifications (PTMs) have been identified in a-syn within LBs and under physiological conditions, including phosphorylation, mono-and poly-ubiquitination at multiple lysine residues, as well as truncations and nitration, 2 suggesting that these modifications play a role in a-syn aggregation, LB formation. Increasing evidence also suggests that a-syn PTMs play important roles in regulating a-syn degradation by the proteasome or autophagy, subcellular localization and physiological functions.…”

“…Increasing evidence also suggests that a-syn PTMs play important roles in regulating a-syn degradation by the proteasome or autophagy, subcellular localization and physiological functions. 2 Thus, a better understanding of how a-syn PTMs regulate its functions in health and disease is crucial for understanding the biology of a-syn. Achieving this goal requires the ability to obtain homogenous preparations of chemically well-defined a-syn PTMs, which are typically difficult to obtain using conventional biochemical methods that often result in heterogeneous mixtures of products.…”

“…Achieving this goal requires the ability to obtain homogenous preparations of chemically well-defined a-syn PTMs, which are typically difficult to obtain using conventional biochemical methods that often result in heterogeneous mixtures of products. 2 This is due to the fact that the enzymes responsible for many a-syn PTMs are not yet known, thus making it difficult to achieve selective modifications and elucidate the relative contribution of each modification or cross-talk between different PTMs.…”