The Latest Articles on α-Synuclein in Parkinson’s Disease

Our staff editors continue to share exciting, interesting, and thought-provoking reading material in the recommended articles series.

This week, we would like to share several latest articles on α-Synuclein in Parkinson’s Disease.

Title: Loss of monomeric alpha-synuclein (synucleinopenia) and the origin of Parkinson's disease
Authors: Alberto J. Espay, Andrew J. Lees
Type: Review Article

Abstract:
These facts argue against the gain-of-function synucleinopathy hypothesis, which proposes that Lewy pathology causes Parkinson's disease: (1) most brains from people without neurological symptoms have multiple pathologies; (2) neither pathology type nor distribution correlate with disease severity or progression in Parkinson's disease; (3) aggregated α-synuclein in the form of Lewy bodies is not a space-occupying lesion but the insoluble fraction of its precursor, soluble monomeric α-synuclein; (4) pathology spread is passive, occurring by irreversible nucleation, not active replication; and (5) low cerebrospinal fluid α-synuclein levels predict brain atrophy and clinical disease progression. The transformation of α-synuclein into Lewy pathology may occur as a response to biological, toxic, or infectious stressors whose persistence perpetuates the nucleation process, depleting normal α-synuclein and eventually leading to Parkinson's symptoms from neuronal death. We propose testing the loss-of-function synucleinopenia hypothesis by evaluating the clinical and neurodegenerative rescue effect of replenishing the levels of monomeric α-synuclein.
Access this article: https://doi.org/10.1016/j.parkreldis.2024.106077

Title: Gut microbiome, short-chain fatty acids, alpha-synuclein, neuroinflammation, and ROS/RNS: Relevance to Parkinson's disease and therapeutic implications
Authors: Balaraman Kalyanaraman, Gang Cheng, Micael Hardy
Type: Review Article

Abstract
In this review, we explore how short-chain fatty acids (SCFAs) produced by the gut microbiome affect Parkinson's disease (PD) through their modulatory interactions with alpha-synuclein, neuroinflammation, and oxidative stress mediated by reactive oxygen and nitrogen species (ROS/RNS). In particular, SCFAs—such as acetate, propionate, and butyrate—are involved in gut–brain communication and can modulate alpha-synuclein aggregation, a hallmark of PD. The gut microbiome of patients with PD has lower levels of SCFAs than healthy individuals. Probiotics may be a potential strategy to restore SCFAs and alleviate PD symptoms, but the underlying mechanisms are not fully understood. Also in this review, we discuss how alpha-synuclein, present in the guts and brains of patients with PD, may induce neuroinflammation and oxidative stress via ROS/RNS. Alpha-synuclein is considered an early biomarker for PD and may link the gut–brain axis to the disease pathogenesis. Therefore, elucidating the role of SCFAs in the gut microbiome and their impact on alpha-synuclein-induced neuroinflammation in microglia and on ROS/RNS is crucial in PD pathogenesis and treatment.
Access this article: https://doi.org/10.1016/j.redox.2024.103092

Title: MUFA synthesis and stearoyl-CoA desaturase as a new pharmacological target for modulation of lipid and alpha-synuclein interaction against Parkinson's disease synucleinopathy
Authors: Joanna Kula, Katarzyna Z. Kuter
Type: Review Article

Abstract:
Protein pathology spreading within the nervous system, accompanies neurodegeneration and a spectrum of motor and cognitive dysfunctions. Currently available therapies against Parkinson's disease and other synucleinopathies are mostly symptomatic and fail to slow the disease progression in the long term. Modification of α-synuclein (αS) aggregation and toxicity of its pathogenic forms is one of the main goals in neuroprotective approach. Since the discovery of lipid component of Lewy bodies, fatty acids became a crucial, yet little explored target for research. MUFAs (monounsaturated fatty acids) are substrates for lipids, such as phospholipids, triglycerides and cholesteryl esters. They regulate membrane fluidity, take part in signal transduction, cellular differentiation and other fundamental processes. αS and MUFA interactions are essential for Lewy body pathology. αS increases levels of MUFAs, mainly oleic acid, which in turn can enhance αS toxicity and aggregation. Thus, reduction of MUFAs synthesis by inhibition of stearoyl-CoA desaturase (SCD) activity could be the new way to prevent aggravation of αS pathology. Due to the limited distribution in peripheral tissues, SCD5 is a potential target in novel therapies and therefore could be an important starting point in search for disease-modifying neuroprotective therapy. Here we summarize facts about physiology and pathology of αS, explain recently discovered lipid-αS interactions, review SCD function and involved mechanisms, present available SCD inhibitors and discuss their pharmacological potential in disease management. Modulation of MUFA synthesis, decreasing αS and lipid toxicity is clearly essential, but unexplored avenue in pharmacotherapy of Parkinson's disease and synucleinopathies.    
Access this article: https://doi.org/10.1016/j.neuropharm.2024.109865

Title: α-Synuclein seed amplification technology for Parkinson’s disease and related synucleinopathies
Authors: Claudio Soto
Type: Review Article

Abstract:
Synucleinopathies are a group of neurodegenerative diseases (NDs) associated with cerebral accumulation of α-synuclein (αSyn) misfolded aggregates. At this time, there is no effective treatment to stop or slow down disease progression, which in part is due to the lack of an early and objective biochemical diagnosis. In the past 5 years, the seed amplification technology has emerged for highly sensitive identification of these diseases, even at the preclinical stage of the illness. Much research has been done in multiple laboratories to validate the efficacy and reproducibility of this assay. This article provides a comprehensive review of this technology, including its conceptual basis and its multiple applications for disease diagnosis, as well for understanding of the disease biology and therapeutic development.
Access this article: https://doi.org/10.1016/j.tibtech.2024.01.007

Title: Protein–protein interactions regulating α-synuclein pathology
Authors: Jiannan Wang, Lijun Dai, Sichun Chen, Zhaohui Zhang, Xin Fang, Zhentao Zhang
Type: Review Article

Abstract:
Parkinson’s disease (PD) is a neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the formation of Lewy bodies (LBs). The main proteinaceous component of LBs is aggregated α-synuclein (α-syn). However, the mechanisms underlying α-syn aggregation are not yet fully understood. Converging lines of evidence indicate that, under certain pathological conditions, various proteins can interact with α-syn and regulate its aggregation. Understanding these protein–protein interactions is crucial for unraveling the molecular mechanisms contributing to PD pathogenesis. In this review we provide an overview of the current knowledge on protein–protein interactions that regulate α-syn aggregation. Additionally, we briefly summarize the methods used to investigate the influence of protein–protein interactions on α-syn aggregation and propagation.
Access this article: https://doi.org/10.1016/j.tins.2024.01.002