α-Synuclein at the Presynaptic Axon Terminal as a Double-Edged Sword

Abstract

α-synuclein (α-syn) is a presynaptic, lipid-binding protein strongly associated with the neuropathology observed in Parkinson's disease (PD), dementia with Lewy bodies (DLB), and Alzheimer's Disease (AD). In normal physiology, α-syn plays a pivotal role in facilitating endocytosis and exocytosis. Interestingly, mutations and modifications of precise α-syn domains interfere with α-syn oligomerization and nucleation that negatively affect presynaptic vesicular dynamics, protein expressions, and mitochondrial profiles. Furthermore, the integration of the α-syn oligomers into the presynaptic membrane results in pore formations, ion influx, and excitotoxicity. Targeted therapies against specific domains of α-syn, including the use of small organic molecules, monoclonal antibodies, and synthetic peptides, are being screened and developed. However, the prospect of an effective α-syn targeted therapy is still plagued by low permeability across the blood-brain barrier (BBB), and poor entry into the presynaptic axon terminals. The present review proposes a modification of current strategies, which includes the use of novel encapsulation technology, such as lipid nanoparticles, to bypass the BBB and deliver such agents into the brain.

Keywords: Lewy bodies (LB); Parkinson’s disease; dementia with Lewy bodies; presynaptic axon terminal; synaptic vesicle endocytosis; synucleinopathy; targeted therapy; α-synuclein; α-synuclein oligomerization.

Figure 1

Effects of missense mutations on the α-syn structure and physiological functions. A30P may prevent further helical coiling of α-syn helical domain [32,33], reducing α-syn membrane-binding affinity [78,79], and allowing its aggregation within the cytosol E46K removes the salt bridge formation between E46 and K80, allowing the formation of stable protofilament that promotes further fibrillation [80]. Similarly, A53T interrupts distant NAC and N-terminal or C-terminal interactions, leading to protofilament formation [82]. G51D mutations promotes the nuclear localization and hyperphosphorylation of S129 that induces aggregation [59]. Figure is created with BioRender.com.

Figure 2

Physiological roles of α-syn in the presynaptic axon terminal. α-syn plays pivotal roles in the presynaptic axon terminal participating in vesicular clustering [12,18,43], recycling process, such as exocytosis and endocytosis [43,44,48,50,51,52], microtubule alterations [39], as well as maintaining mitochondrial fusion and fission dynamics through cytoskeletal reformation [99,100,101,114]. Figure is created with BioRender.com.

Figure 3

Putative effects of pathogenic α-syn in the presynaptic axon terminal. α-syn monomers forms trimers [27,41], which further oligomerizes to form amyloid fibrils [41], or β-sheet-like pores at the cell membrane [36,37]. Fibrils may interfere with cytoskeletal polymerization and depolymerization dynamics [97,98,101], mitochondrial fusion/fission dynamics [101,105,106], impairs clathrin-mediated endocytosis [27], and inhibiting autophagic systems [38,90,91], to cause a pleiotropic range of effects on the presynaptic axon terminal. Furthermore, α-syn fibrils may be released and taken in at the presynaptic axon terminal [110,111,119], suggesting the bidirectional transport of α-syn across neuronal synapses. Figure is created with BioRender.com.