Introduction

α-Synuclein is a major constituent of Lewy bodies (LBs) and Lewy neurites (LNs), which are pathological hallmarks of synucleinopathies, including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) (Spillantini et al. 1998; Dickson 2001; Stefanis 2012). Several missense mutations, as well as duplicate and triplicate regions of the α-synuclein gene are responsible for familial PD (Polymeropoulos et al. 1997; Zarranz et al. 2004; Kruger et al. 1998; Singleton et al. 2003; Chartier-Harlin et al. 2004). In studies of α-synuclein pathogenicity, it was demonstrated that overexpression of α-synuclein in neurons results in the formation of inclusion bodies and neuronal loss (Masliah et al. 2000; Van der Perren et al. 2015; Singleton et al. 2003). Therefore, an increase in the intracellular amount of α-synuclein is a probable risk factor for neurodegeneration.

Expression of α-synuclein is regulated by various transcription factors, such as zinc finger and SCAN domain containing 21 (ZSCAN21) (Clough et al. 2009; Dermentzaki et al. 2016), GATA-1 and GATA-2 (Scherzer et al. 2008), Nurr1 (Yang and Latchman 2008), TRIM32 (Pavlou et al. 2017), and p27Kip1 (Gallastegui et al. 2018). These transcription factors interact directly with the promotor region of α-synuclein, and this critical link between these transcription factors and α-synuclein may enable the design of therapies to lower production of α-synuclein. Further studies of the regulation machinery of α-synuclein expression via these transcription factors will help develop novel therapeutic strategies for synucleinopathies.

According to a recent study, β2-adrenoreceptor (β2AR) was identified as a novel regulator of the α-synuclein gene (Mittal et al. 2017). β2AR activation by selective agonists reduces α-synuclein expression in mouse substantia nigra. Conversely, suppression of β2AR expression or chemical inhibition of β2AR activity increases α-synuclein expression. Furthermore, longitudinal studies of incident PD throughout Norway showed that the β2AR antagonist, propranolol, is associated with a markedly increased risk of PD. However, salbutamol, a β2AR agonist, is associated with a decreased risk of PD. Thus, fine-tuning of intrinsic α-synuclein expression levels could constitute an innovative therapeutic strategy to prevent PD onset.

Expression levels and subcellular distribution of α-synuclein in each neuronal cell type are related closely to the pathogenicity and the physiological function of α-synuclein. In this review, we focus on the characteristic profile of α-synuclein expression in vitro and in vivo, and further discuss new findings obtained from recent studies on this protein.

Differential expression of α-synuclein under physiological conditions

α-Synuclein is enriched in brain and is localized at presynapses under physiologically normal conditions in vitro and in vivo (Withers et al. 1997; Totterdell et al. 2004; Totterdell and Meredith 2005; Vivacqua et al. 2011). It has been suggested that α-synuclein plays a role in the generation and maintenance of synapses because this protein appears earlier than synaptophysin—a synaptic vesicle protein—during development of the central nervous system (CNS) and is localized to axon terminals throughout the adult mammalian brain (Hsu et al. 2014). The hippocampal CA is a region significantly affected by α-synuclein pathology in advanced PD and DLB compared with the DG (Armstrong et al. 2014; Hall et al. 2014). Interestingly, Math2-expressing CA neurons show higher levels of α-synuclein expression, whereas Prox1-expressing DG neurons express low levels of α-synuclein and are resistant relative to the Math2-expressing subpopulations (Luna et al. 2018). These results indicate that PFF-induced cell susceptibility is closely related to the endogenous expression levels of α-synuclein, which are regulated differentially in each neuronal cell-type.

In postmortem human brains, regional levels of physiological α-synuclein are directly associated with LB pathology (Erskine et al. 2018). Quantitative imaging and western blotting analysis demonstrated that brain regions less relevant to LB pathology, such as primary visual cortex and cerebellar cortex, show strikingly lower expression levels of α-synuclein. Recruitment of soluble α-synuclein into the intracellular aggregates is required for the process of pathological LB propagation in brain, as described above. Therefore, these results are consistent with previous studies using various in vitro and in vivo models. However, brain regions with the greatest proclivity to LB pathology did not have the highest levels of endogenous α-synuclein expression, and it was suggested that expression levels of α-synuclein are not the sole determinants of cell vulnerability. Vulnerability to LB pathology is the product of anatomical connectivity and region autonomous factors, with a baseline level of physiological α-synuclein expression necessary for pathology to develop (Erskine et al. 2018). For instance, higher α-synuclein expression is observed within the cell bodies of dopamine neurons in both the SNC and ventral tegmental area (VTA). However, dopaminergic neurons in the VTA are much less affected in PD. This difference might not be attributable to the expression levels of α-synuclein, however, because the difference in pacemaking mechanisms and engagement of L-type calcium channels in neurons of the SNC and VTA has been reported to cause a difference in their vulnerability (Guzman et al. 2010; Khaliq and Bean 2010).

Conclusion

High expression of α-synuclein is a critical risk factor for aggregate formation and neuronal loss (Fig. 8). Accumulated evidence suggests the close relationship between differential expression of α-synuclein and selective vulnerability of certain neuronal populations. Factors other than α-synuclein expression level may also be involved in vulnerability. Further investigation of the regulation of α-synuclein expression will help understand the mechanism of LB pathology and provide an innovative therapeutic strategy to prevent PD and DLB onset.

Fig. 8
figure 8

Models of the relationship between α-synuclein expression levels and Lewy body (LB) formation. a LB formed by recruitment of endogenous soluble αSyn into the insoluble aggregate core. b Neurons with low expression of αSyn are spared from LB pathology

Full size image