Date Published: October 25, 2018
Publisher: Springer Singapore
Author(s): Katsutoshi Taguchi, Yoshihisa Watanabe, Atsushi Tsujimura, Masaki Tanaka.
α-Synuclein, the major component of Lewy bodies (LBs) and Lewy neurites (LNs), is expressed in presynapses under physiologically normal conditions and is involved in synaptic function. Abnormal intracellular aggregates of misfolded α-synuclein such as LBs and LNs are pathological hallmarks of synucleinopathies, including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). According to previous studies using pathological models overexpressing α-synuclein, high expression of this protein in neurons is a critical risk factor for neurodegeneration. Therefore, it is important to know the endogenous expression levels of α-synuclein in each neuronal cell type. We previously reported differential expression profiles of α-synuclein in vitro and in vivo. In the wild-type mouse brain, particularly in vulnerable regions affected during the progression of idiopathic PD, α-synuclein is highly expressed in neuronal cell bodies of some early PD-affected regions, such as the olfactory bulb, the dorsal motor nucleus of the vagus, and the substantia nigra pars compacta. Synaptic expression of α-synuclein is mostly accompanied by expression of vesicular glutamate transporter-1, an excitatory synapse marker protein. In contrast, α-synuclein expression in inhibitory synapses differs among brain regions. Recently accumulated evidence indicates the close relationship between differential expression profiles of α-synuclein and selective vulnerability of certain neuronal populations. Further studies on the regulation of α-synuclein expression will help to understand the mechanism of LB pathology and provide an innovative therapeutic strategy to prevent PD and DLB onset.
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.
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. 8Models 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