Synucleins and Gene Expression: Ramblers in a Crowd or Cops Regulating Traffic?

Abstract

Synuclein family consists of three members, α, β, and γ-synuclein. Due to their involvement in human diseases, they have been thoroughly investigated for the last 30 years. Since the first synuclein identification and description, members of this family are found in all vertebrates. Sequencing of their genes indicates high evolutionary conservation suggesting important function(s) of these proteins. They are small naturally unfolded proteins prone to aggregate, easily change their conformation, and bind to the membranes. The genes for α, β, and γ-synuclein have different chromosomal localization and a well preserved general organization composed of five coding exons of similar size. Three genes encoding synucleins are present in the majority of vertebrates, however, a variable number of synuclein genes are described in fishes of different species. An important question concerns their normal function in cells and tissues. α-Synuclein is implicated in the regulation of synaptic activity through regulation of synaptic vesicle release, while the physiological functions of two other members of the family is understood less clearly. Here we discuss recent results describing their role in the regulation of gene expression.

Keywords: DNA methylation; epigenetic regulation; gene expression; histone modifications; neurodegeneration; synucleins; transcription factors; translation factors.

FIGURE 1

Identification of α-synuclein-interacting proteins by peroxidase labeling technique coupled with mass spectrometry. A genetically engineered peroxidase APEX tagged to the C-terminal of wild-type α-synuclein defines the protein network in the vicinity (10 nm) of α-synuclein in living neurons. In addition to anticipated α-synuclein-interacting proteins involved in synaptic transmission and endocytosis, this method reveals several mRNA binding proteins implicated in mRNA translation. Adapted from Chung et al. (2017) with permission from the copyright holder.

FIGURE 2

Proteins involved in mRNA translation labeled by α-synuclein-APEX. mRNA translation-related proteins are tested for physical interaction with α-synuclein using the membrane-2-hybrid (MYTH) technique. For example, multiple subunits of translation initiation factor EIF3 are labeled with α-synuclein-APEX and stain positive for MYTH. From the list of mRNA translation hits in the APEX neuron study, five were available for testing by MYTH. Four of those, namely EIF3C, EIF3L, RPS12, and PABPC1 were confirmed. These data imply that mRNA translation machinery elements and binding proteins are in close proximal interactions with α-synuclein. Adapted from Chung et al. (2017) with permission from the copyright holder.

FIGURE 3

Association of α-synuclein with histones in the cell nucleus induces formation of α-synuclein fibrils. Importantly, inhibition of H3 histone acetylation by α-synuclein affects the expression level of genes responsible for cell survival. Furthermore, association of α-synuclein with p300 decreases HAT activity. Binding of α-synuclein to DNA affects the expression of several genes, e.g., NOTCH1 and PGC-1A, and may lead to DNA damage. It allows the preservation of associated MCM2-7 complexes on the chromatin. Ac, acetylation; PTMs, post-translational modifications. Adapted from Pavlou et al. (2017) with permission from the copyright holder.