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Synucleins: What do they do in the Nucleus?

Andrei Surguchov

Professor, Retinal Biology Research Laboratory, VA Medical Center

Corresponding author

Andrei Surgucov, Professor, Retinal Biology Research Laboratory, VA Medical Center, 4801 East Linwood Boulevard, Kansas City, MO, 64128, Tel: 816-861-4700 x 57078; Fax : 816-861-1110; E-mail: asurguchov@kumc.edu

Received Date: 03 May 2014

Accepted Date: 06 May 2014

Published Date: 10 May 2014


Giroh L, Tong Y, Sun W (2014) Chinese Cancer Status - Challenge and Opportunity. Enliven: Challenges Cancer 1(1): e001.


@ 2014 Dr. Wenjie Sun. This is an Open Access article published and distributed under the terms of the Creative Commons Attribution License that permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.

Synucleins are small (113–143 amino acids) proteins expressed primarily in neural tissue. The family consists of three proteins: α -synuclein, β -synuclein, and γ-synuclein with high amino acid sequence similarity at the N-termini and variable C-termini. All synucleins have in common a highly conserved alpha-helical lipid-binding motif [1].

For almost 26 years since the discovery of the first synuclein by Maroteaux et al. [2] a main question and a main direction of their studies was to understand synuclein’s normal function(s). The role of these proteins in human diseases was established much earlier: α-synuclein was implicated in Parkinson’s disease and several other neurodegenerative disorders [3], whereas γ-synuclein was associated with several types of cancer [4] and some neurodegenerative disorders [1].

Several studies pointed to a role of α-synuclein in synaptic transmission. α-Synuclein may act as a chaperone, assisting in the folding and refolding of synaptic proteins called SNAREs. These proteins are crucial for release of neurotransmitters at the neuronal synapse, vesicle recycling, and synaptic integrity [4]. These results may explain at least partially what synuclein’s functions in synapsis are. However, in addition to synaptic localization, synucleins have been detected in the nucleus. In spite of the absence of nuclear targeting sequences nuclear localization has been described for all three forms of synucleins: α-synuclein [5-7], β-synuclein [8] and γ-synuclein [9].

Nuclear localization of α-synuclein have been described in a variety of experimental systems, including transgenic Drosophila [10], mice [11,12], and cultured cells [13,14]. β-Synuclein is revealed in nuclei of human astrocytes in culture [8], while γ-synuclein in nuclei of several types of cultured cells [15]. The question arises when and why synuclein are translocated to the nucleus?

Increasing evidence indicates that synucleins participate in the regulation of gene expression (Figure 1) in response to changing conditions. For example, α-synuclein downregulates c-Jun N-terminal kinase protecting cells against oxidative stress, upregulates caveolin-1 expression and downregulates ERK expression which may play a role in the pathogenesis of Parkinson disease [16,17].

In another publication α-synuclein effect in reducing Bcl-xL expression and increasing bax expression was described [18]. Importantly α-synuclein is able to directly bind to promoter region of specific genes and affect the transcription of selected genes. For example Siddiqui et al. [19] described α-synuclein binding to a promoter of the transcriptional co-activator PGC-1α which reduces its expression in response to oxidative stress.

γ-Synuclein is also a modulator of specific genes expression. For example, it significantly upregulates matrix metalloproteinases-9 (MMP 9) expression and activity. This effect is mediated via γ-synuclein binding to AP-1 binding sites in the promoter region of the MMP-9 gene [20].

Under stress conditions a translocation of γ-synuclein to the nucleus reduces neurite outgrowth in a greater extent than α-synuclein overexpression [20]. These data support the view that γ-synuclein may change its intracellular localization in response to stress and make appropriate alterations in the gene expression pattern.

Therefore, synucleins can be targeted to the nucleus in response to stress and reprogram the pattern of gene expression. Thus, nuclear translocation of synuclein can be considered as a target for therapeutic intervention.


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