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      Alternative Splicing of Alpha- and Beta-Synuclein Genes Plays Differential Roles in Synucleinopathies

      review-article
      , *
      Genes
      MDPI
      α-synuclein, SNCA, β-synuclein, SNCB, alternative splicing, functional splice variants, differential expression

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          Abstract

          The synuclein family is composed of three members, two of which, α- and β-synuclein, play a major role in the development of synucleinopathies, including Parkinson’s disease (PD) as most important movement disorder, dementia with Lewy bodies (DLB) as the second most frequent cause of dementia after Alzheimer’s disease and multiple system atrophy. Whereas abnormal oligomerization and fibrillation of α-synuclein are now well recognized as initial steps in the development of synucleinopathies, β-synuclein is thought to be a natural α-synuclein anti-aggregant. α-synuclein is encoded by the SNCA gene, and β-synuclein by SNCB. Both genes are homologous and undergo complex splicing events. On one hand, in-frame splicing of coding exons gives rise to at least three shorter transcripts, and the functional properties of the corresponding protein isoforms are different. Another type of alternative splicing is the alternative inclusion of at least four initial exons in the case of SNCA, and two in the case of SNCB. Finally, different lengths of 3’ untranslated regions have been also reported for both genes. SNCB only expresses in the brain, but some of the numerous SNCA transcripts are also brain-specific. With the present article, we aim to provide a systematic review of disease related changes in the differential expression of the various SNCA and SNCB transcript variants in brain, blood, and non-neuronal tissue of synucleinopathies, but especially PD and DLB as major neurodegenerative disorders.

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          Most cited references130

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          miRDB: an online resource for microRNA target prediction and functional annotations

          MicroRNAs (miRNAs) are small non-coding RNAs that are extensively involved in many physiological and disease processes. One major challenge in miRNA studies is the identification of genes regulated by miRNAs. To this end, we have developed an online resource, miRDB (http://mirdb.org), for miRNA target prediction and functional annotations. Here, we describe recently updated features of miRDB, including 2.1 million predicted gene targets regulated by 6709 miRNAs. In addition to presenting precompiled prediction data, a new feature is the web server interface that allows submission of user-provided sequences for miRNA target prediction. In this way, users have the flexibility to study any custom miRNAs or target genes of interest. Another major update of miRDB is related to functional miRNA annotations. Although thousands of miRNAs have been identified, many of the reported miRNAs are not likely to play active functional roles or may even have been falsely identified as miRNAs from high-throughput studies. To address this issue, we have performed combined computational analyses and literature mining, and identified 568 and 452 functional miRNAs in humans and mice, respectively. These miRNAs, as well as associated functional annotations, are presented in the FuncMir Collection in miRDB.
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            alpha-Synuclein is phosphorylated in synucleinopathy lesions.

            The deposition of the abundant presynaptic brain protein alpha-synuclein as fibrillary aggregates in neurons or glial cells is a hallmark lesion in a subset of neurodegenerative disorders. These disorders include Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy, collectively referred to as synucleinopathies. Importantly, the identification of missense mutations in the alpha-synuclein gene in some pedigrees of familial PD has strongly implicated alpha-synuclein in the pathogenesis of PD and other synucleinopathies. However, specific post-translational modifications that underlie the aggregation of alpha-synuclein in affected brains have not, as yet, been identified. Here, we show by mass spectrometry analysis and studies with an antibody that specifically recognizes phospho-Ser 129 of alpha-synuclein, that this residue is selectively and extensively phosphorylated in synucleinopathy lesions. Furthermore, phosphorylation of alpha-synuclein at Ser 129 promoted fibril formation in vitro. These results highlight the importance of phosphorylation of filamentous proteins in the pathogenesis of neurodegenerative disorders.
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              HITS-CLIP yields genome-wide insights into brain alternative RNA processing

              Summary Protein-RNA interactions play critical roles in all aspects of gene expression. Here we develop a genome-wide means of mapping protein-RNA binding sites in vivo, by high throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP). HITS-CLIP analysis of the neuron-specific splicing factor Nova2 revealed extremely reproducible RNA binding maps in multiple mouse brains. These maps provide genome-wide in vivo biochemical footprints confirming the previous prediction that the position of Nova binding determines the outcome of alternative splicing; moreover, they are sufficiently powerful to predict Nova action de novo. HITS-CLIP revealed a large number of Nova-RNA interactions in 3′ UTRs, leading to the discovery that Nova regulates alternative polyadenylation in the brain. HITS-CLIP, therefore, provides a robust, unbiased means to identify functional protein-RNA interactions in vivo.
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                Author and article information

                Journal
                Genes (Basel)
                Genes (Basel)
                genes
                Genes
                MDPI
                2073-4425
                25 January 2018
                February 2018
                : 9
                : 2
                : 63
                Affiliations
                Department of Pathology, Germans Trias i Pujol Research Institute, Badalona, 08916 Barcelona, Spain; avalero@ 123456igtp.cat
                Author notes
                [* ]Correspondence: kbeyer@ 123456igtp.cat ; Tel.: +34-93-497-8853
                Author information
                https://orcid.org/0000-0002-9530-2751
                Article
                genes-09-00063
                10.3390/genes9020063
                5852559
                29370097
                4f50ae18-1012-46d2-9a3a-bad9c8ddb004
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 03 November 2017
                : 17 January 2018
                Categories
                Review

                α-synuclein,snca,β-synuclein,sncb,alternative splicing,functional splice variants,differential expression

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