|A Novel Function of
α-Synuclein at the Axon Initial Segment
α-Synuclein is a small protein comprising 140 amino acids. It is the major component in the pathological inclusion bodies (called "Lewy bodies") of Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Dementia refers to the loss of cognitive functioning—thinking, remembering, and reasoning. Thus, the familial PD resulting from several α-synuclein mutations exhibits both classic motor deficits (resting tremor, rigidity, etc.) and cognitive impairment (hallucination and dementia) (Zarranz et al., 2004; Dehay et al., 2015).
α-Synuclein is widely distributed in the brain, particularly at presynaptic terminals (Taguchi et al., 2019). This led previous studies to focus on its role in neurotransmitter release from presynaptic terminals (Benskey et al., 2016; Butler et al., 2017). α-Synuclein is also present in axons (Kokhan et al., 2012), where it may regulate microtubule polymerization (Alim et al., 2004; Cartelli et al., 2016), but exactly how α-synuclein can influence motor and cognitive functions via microtubule polymerization remains unclear.
In the Wireless Communication Model, microtubules are proposed to act as receiving antennas, which requires microtubules at the axon initial segment (AIS) to move toward or away from the membrane in response to electromagnetic forces. Intrinsically, microtubules may switch between assembly and disassembly, depending on the concentration of free tubulin. This property is known as "dynamic instability". Microtubule stability also depends on post-translational modifications of tubulin (polyamination, acetylation, tyrosination, etc.) and binding of microtubule associated proteins. The microtubules serving as receiving antennas should be stable, mobile, and shorter than the length of AIS, which varies from 10 to 60 μm (Gutzmann et al., 2014; Höfflin et al., 2017). Remarkably, such unconventional microtubules have been discovered several decades ago. They are referred to as "transportable microtubules" (Brady et al., 1984; Baas, 2013; Baas et al., 2016).
α-Synuclein Promotes Assembly of Transportable Microtubules
Recently, α-synuclein has been demonstrated to promote the assembly of transportable microtubules (tMTs) (Toba et al., 2017). Synucleins have three isoforms: α, β and γ. In the absence of synucleins, the lengths of assembled microtubules vary widely, from 5 µm to 95 µm. The presence of α-synuclein results in narrow distribution of microtubule lengths, with peak at 15 µm. β- and γ-synuclein also produce narrower distribution, but to a less degree than α-synuclein (Figure 1).
Several α-synuclein mutations are linked to PD, such as the E46K mutation (Zarranz et al., 2004), where the amino acid glutamate (E) at position 46 is replaced by lysine (K). Another example is the A30P mutation (Krüger et al., 1998). Strikingly, these mutations abolish the effects of α-synuclein on microtubule polymerization, that is, the short microtubules no longer dominate (Figure 1g, h). Hence, the familial PD could result from decreased number of tMTs.
Approximately 90% of α-synuclein found in Lewy bodies are phosphorylated at serine-129 (S129) (Sato et al., 2011; Oueslati, 2016). This demonstrates the importance of S129 phosphorylation in PD. Phosphorylation is a process that adds a negatively charged phosphate group (PO43-) to an amino acid in a protein. Glutamate (E) is also negatively charged while alanine (A) is a neutral amino acid. Thus, the mutation S129E, but not S129A, mimics the effects of S129 phosphorylation. Interestingly, the mutation S129E, but not S129A, also abolishes the effects of α-synuclein on microtubule polymerization (Figure 1f). Therefore, idiopathic PD (without known cause) could also result from decreased number of tMTs.
Loss of tMTs Can Alter Long-Range Coupling
Brain waves arise from large scale long-range synchronization. Their power should be altered by the loss of functional α-synuclein, if tMTs at AIS indeed serve as receiving antennas during wireless communication. Generally, the decreased number of tMTs at AIS is expected to reduce long-range electromagnetic coupling, thereby attenuating the power of brain waves. This prediction is consistent with the following reports:
In PD, although the cortical beta power is decreased (Caviness et al., 2016; He et al., 2017), the beta activity in subthalamic nucleus (STN) is exaggerated (Tinkhause et al., 2018). As discussed in this article, the beta activity in STN could be mediated by somatostatin-positive GABAergic interneurons (SOM cells) which do not express α-synuclein (Taguchi et al., 2019). Therefore, long-range coupling with SOM cells is not regulated by α-synuclein, but by Parkin.
Glycogen synthase kinase-3β (GSK-3β) has been shown to phosphorylate α-synuclein at S129 (Credle et al., 2015). This may explain why GSK-3β is implicated in PD (Cartelli et al., 2012; Li et al., 2014; Golpich et al., 2015). Further details are discussed in another article.
Author: Frank Lee