Mechanisms of alpha-synuclein toxicity: An update and outlook

Alpha-Synuclein: Mechanisms of Release and Pathology Progression in Synucleinopathies

“…The synuclein family comprises three small soluble proteins, alpha-, beta-and gamma-synuclein, that bind to phospholipid membranes [22]. aSyn is encoded by the SNCA gene and is composed of three distinct domains, which are defined on their amino acid composition: the N-terminal lipid-binding domain, an amyloid-binding central region (NAC), and a C-terminal disordered region [23]. The N-terminal domain is positively charged and contains seven amphipathic repeats containing a conserved KTKEGV hexameric motif, which enables an alpha-helical structure and interactions with membranes [24,25].…”

“…The specific factors that trigger aSyn aggregation still remain unclear. Mutations, expression levels, clearance efficiency, saturation of membranes, environmental factors, interactions with other amyloidogenic proteins, and/or with intermediary toxic species, truncation, or post-translational modifications are among the myriad of possible factors [23].…”

“…The pathological consequences of aSyn dyshomeostasis may themselves exacerbate such dyshomeostasis. These include dysregulation of mitochondrial activity, impairment of endoplasmic reticulum (ER)-Golgi and of synaptic vesicle trafficking, disruption of plasma membrane integrity, impairment of protein clearance systems, or impaired immune system and inflammation responses [23,53,54].…”

The Role of the Microbiome in Central Nervous System Clinical Pharmacology: More Than a Gut Feeling

“…1 It was already proposed two decades ago that so-called Lewy bodies, which are toxic aggregates in the brain of the protein α-synuclein (αSYN) involved in the pathogenesis of Parkinson's disease (PD), may originate in the gut and travel to the CNS through vagal fibers innervating the enteric nervous system (ENS). 6 More recently, a role of the microbiome has been postulated in PD and other neurodegenerative diseases. 7 Hawkins et al 1 argue that current methods in this area, such as in vitro bacterial cultures and preclinical in EDITORIAL vivo models, are insufficient to capture the details of the mechanistic complexity required for efficient drug discovery and development and make the case that clinical pharmacologists should embrace a combination of in vitro human organ-on-a-chip/microphysiological models, 8 multi-omics, 9 and in silico (QSP) computational approaches.…”

“…However, the most intriguing and important question is of course, “What does the microbiome do to the body (and can we influence this pharmacologically)?” In this issue of Clinical Pharmacology & Therapeutics , Hawkins and coworkers present a comprehensive overview of the role of the microbiome‐gut‐liver‐immune‐brain axis (M‐GLIBA, Figure ) in the central nervous system (CNS) and the challenges and opportunities for clinical pharmacologists 1 . It was already proposed two decades ago that so‐called Lewy bodies, which are toxic aggregates in the brain of the protein α‐synuclein (αSYN) involved in the pathogenesis of Parkinson's disease (PD), may originate in the gut and travel to the CNS through vagal fibers innervating the enteric nervous system (ENS) 6 . More recently, a role of the microbiome has been postulated in PD and other neurodegenerative diseases 7 .…”