Mechanisms of alpha-synuclein toxicity: An update and outlook.

Alpha-synuclein (aSyn) was identified as the main component of inclusions that define synucleinopathies more than 20 years ago. Since then, aSyn has been extensively studied in an attempt to unravel its roles in both physiology and pathology. Today, studying the mechanisms of aSyn toxicity remains in the limelight, leading to the identification of novel pathways involved in pathogenesis. In this chapter, we address the molecular mechanisms involved in synucleinopathies, from aSyn misfolding and aggregation to the various cellular effects and pathologies associated. In particular, we review our current understanding of the mechanisms involved in the spreading of aSyn between different cells, from the periphery to the brain, and back. Finally, we also review recent studies on the contribution of inflammation and the gut microbiota to pathology in synucleinopathies. Despite significant advances in our understanding of the molecular mechanisms involved, we still lack an integrated understanding of the pathways leading to neurodegeneration in PD and other synucleinopathies, compromising our ability to develop novel therapeutic strategies.

Synucleinopathies: Where we are and where we need to go.

Synucleinopathies are a group of disorders characterized by the accumulation of inclusions rich in the a-synuclein (aSyn) protein. This group of disorders includes Parkinson's disease, dementia with Lewy bodies (DLB), multiple systems atrophy, and pure autonomic failure (PAF). In addition, genetic alterations (point mutations and multiplications) in the gene encoding for aSyn (SNCA) are associated with familial forms of Parkinson's disease, the most common synucleinopathy. The Synuclein Meetings are a series that has been taking place every 2 years for about 12 years. The Synuclein Meetings bring together leading experts in the field of Synuclein and related human conditions with the goal of discussing and advancing the research. In 2019, the Synuclein meeting took place in Ofir, a city in the outskirts of Porto, Portugal. The meeting, entitled "Synuclein Meeting 2019: Where we are and where we need to go", brought together >300 scientists studying both clinical and molecular aspects of synucleinopathies. The meeting covered a many of the open questions in the field, in a format that prompted open discussions between the participants, and underscored the need for additional research that, hopefully, will lead to future therapies for a group of as of yet incurable disorders. Here, we provide a summary of the topics discussed in each session and highlight what we know, what we do not know, and what progress needs to be made in order to enable the field to continue to advance. We are confident this systematic assessment of where we stand will be useful to steer the field and contribute to filling knowledge gaps that may form the foundations for future therapeutic strategies, which is where we need to go.

Glycation in Huntington's Disease: A Possible Modifier and Target for Intervention.

Glycation is the non-enzymatic reaction between reactive dicarbonyls and amino groups, and gives rise to a variety of different reaction products known as advanced glycation end products (AGEs). Accumulation of AGEs on proteins is inevitable, and is associated with the aging process. Importantly, glycation is highly relevant in diabetic patients that experience periods of hyperglycemia. AGEs also play an important role in neurodegenerative diseases including Alzheimer's (AD) and Parkinson's disease (PD). Huntington's disease (HD) is a hereditary neurodegenerative disease caused by an expansion of a CAG repeat in the huntingtin gene. The resulting expanded polyglutamine stretch in the huntingtin (HTT) protein induces its misfolding and aggregation, leading to neuronal dysfunction and death. HD patients exhibit chorea and psychiatric disturbances, along with abnormalities in glucose and energy homeostasis. Interestingly, an increased prevalence of diabetes mellitus has been reported in HD and in other CAG triplet repeat disorders. However, the mechanisms underlying the connection between glycation and HD progression remain unclear. In this review, we explore the possible connection between glycation and proteostasis imbalances in HD, and posit that it may contribute to disease progression, possibly by accelerating protein aggregation and deposition. Finally, we review therapeutic interventions that might be able to alleviate the negative impact of glycation in HD.

Yeast-Based Screens to Target Alpha-Synuclein Toxicity.

The budding yeast Saccharomyces cerevisiae (S. cerevisiae) has been a remarkable experimental model for the discovery of fundamental biological processes. The high degree of conservation of cellular and molecular processes between the budding yeast and higher eukaryotes has made it a valuable system for the investigation of the molecular mechanisms behind various types of devastating human pathologies. Genetic screens in yeast provided important insight into the toxic mechanisms associated with the accumulation of misfolded proteins. Thus, using yeast genetics and high-throughput screens, novel molecular targets with therapeutic potential have been identified. Here, we describe a yeast screen protocol for the identification of genetic modifiers of alpha-synuclein (aSyn) toxicity, thereby accelerating the identification of novel potential targets for intervention in Parkinson's disease (PD) and other synucleinopathies.

Sensing α-Synuclein From the Outside via the Prion Protein: Implications for Neurodegeneration.

Parkinson's disease and other synucleinopathies are characterized by the accumulation of aggregated α-synuclein in intracellular proteinaceous inclusions. The progressive nature of synucleinopathies seems to be related to the cell-to-cell spreading of α-synuclein pathology, and several possible mechanisms have been put forward to explain this phenomenon. In our recent study, we found that α-synuclein oligomers interact with cellular prion protein in glutamatergic synapses. This interaction triggered a signaling cascade involving phosphorylation of Fyn kinase and activation of the N-methyl-d-aspartate receptor, thereby leading to synaptic dysfunction. Here, we present relevant plasma membrane proteins that have been described to interact with α-synuclein and discuss the possible pathological implications. We focus primarily on the prion protein and propose a pathological mechanism in which the interaction between α-synuclein and prion protein leads to the formation of cofilin/actin rods, culminating in long-term potentiation impairment and cognitive dysfunction. We posit that deciphering the mechanisms involved in sensing specific forms of extracellular α-synuclein and transducing this information may prove invaluable in our quest to devise novel diagnostic and therapeutic approaches in PD and other synucleinopathies. © 2018 International Parkinson and Movement Disorder Society.

Identification of novel protein phosphatases as modifiers of alpha-synuclein aggregation in yeast.

Alpha-synuclein (aSyn) is a key player in a group of neurodegenerative diseases commonly known as synucleinopathies. Recent findings indicate phosphorylation in several aSyn residues can modulate its aggregation and subcellular localization, thereby affecting pathological processes. However, the precise molecular mechanisms governing aSyn phosphorylation are still unclear. Recent studies investigated the role of various families of protein kinases, such as the polo-like kinases, G protein-coupled receptor kinases or casein kinases. In contrast, our understanding of the phosphatases involved in the dephosphorylation of aSyn is rather limited. Here, we exploited the unique toolbox of the yeast Saccharomyces cerevisiae in order to identify novel phosphatases capable of modulating aSyn phosphorylation, inclusion formation and toxicity of human aSyn. In summary, given the association between aSyn phosphorylation and pathology in Parkinson's disease and other synucleinopathies, modulation of this post-translational modification may constitute an attractive target for therapeutic intervention.