Alpha synuclein post translational modifications: potential targets for Parkinson’s disease therapy?

Abstract

Parkinson’s disease (PD) is the most common neurodegenerative disorder with motor symptoms. The neuropathological alterations characterizing the brain of patients with PD include the loss of dopaminergic neurons of the nigrostriatal system and the presence of Lewy bodies (LB), intraneuronal inclusions that are mainly composed of alpha-synuclein (α-Syn) fibrils. The accumulation of α-Syn in insoluble aggregates is a main neuropathological feature in PD and in other neurodegenerative diseases, including LB dementia (LBD) and multiple system atrophy (MSA), which are therefore defined as synucleinopathies. Compelling evidence supports that α-Syn post translational modifications (PTMs) such as phosphorylation, nitration, acetylation, O-GlcNAcylation, glycation, SUMOylation, ubiquitination and C-terminal cleavage, play important roles in the modulation α-Syn aggregation, solubility, turnover and membrane binding. In particular, PTMs can impact on α-Syn conformational state, thus supporting that their modulation can in turn affect α-Syn aggregation and its ability to seed further soluble α-Syn fibrillation. This review focuses on the importance of α-Syn PTMs in PD pathophysiology but also aims at highlighting their general relevance as possible biomarkers and, more importantly, as innovative therapeutic targets for synucleinopathies. In addition, we call attention to the multiple challenges that we still need to face to enable the development of novel therapeutic approaches modulating α-Syn PTMs.

Changes in α-Synuclein Posttranslational Modifications in an AAV-Based Mouse Model of Parkinson’s Disease

“…Nevertheless, our findings indicate that the AAV-hα-Syn-based mouse model of PD represents a valuable experimental platform to investigate the role of α-Syn PTM as well as their impact on α-Syn aggregation and on neuronal function and toxicity. In light of the fact that α-Syn PTMs are emerging as possible therapeutic targets to cure PD [15], their characterization in experimental models may help the development of novel approaches to slow down disease progression. Moreover, by expanding our understanding on the occurrence and progression of α-Syn PTM, the result of this study can implement our knowledge on the biological basis of PD and enable a better interpretation of the results from the multitude of toolkits that have been developed to assess whether α-Syn PTM can be considered as potential biomarkers for disease progression and differential diagnosis [60,[80][81][82][83][84][85][86][87][88].…”

“…Indeed, they can affect α-Syn aggregation propensity, solubility and turnover, membrane binding and interaction with other proteins and metals [9][10][11][12][13][14]. Phosphorylation, nitration, acetylation, ubiquitination, SUMOylation, O-GlcNAcylation and glycation are the most studied PTMs and may occur in the pathogenesis of PD [15].…”

“…In particular, α-Syn can be phosphorylated at serine (Ser87 and Ser129) or tyrosine (Tyr125, Tyr133 and Tyr136) residues [15]. Among them, Ser129 is the most studied α-Syn PTM, as it is considered a marker of mature fibrillary aggregates [16,17].…”

Protein Oxidative Modifications in Neurodegenerative Diseases: From Advances in Detection and Modelling to Their Use as Disease Biomarkers

“…Therefore, the simultaneous alterations in these various redox-PTMs strongly suggest an intricate regulation of their crosstalk in redox signalling and maintenance of sulfhydryl homeostasis. Additionally, several PTMs have also been shown to be able to influence protein aggregation [ 189 ], with a paradigmatic example being α-syn aggregation in PD [ 190 , 191 ]. Together, the effects in protein redox regulation and modulation of protein aggregation highlight the relevance of redox-PTMs in age-related NDDs.…”

The Effects of Lipids on α-Synuclein Aggregation In Vitro

“…Furthermore, the more rapidly aggregating αS variant dictated the lag time in mixed preparations of A 30 P or A 53 T and WT αS [54]. There is substantial evidence suggesting that various PTMs of αS significantly influence αS's aggregation ability [55,56]. For example, phosphorylation at serine 129 is a defining hallmark of PD and promotes aggregation [57], while SUMOylation impairs αS ubiquitination and prevents αS degradation, promoting its aggregation [58].…”