Splicing: is there an alternative contribution to Parkinson's disease? - PubMed (original) (raw)

Review

Splicing: is there an alternative contribution to Parkinson's disease?

Valentina La Cognata et al. Neurogenetics. 2015 Oct.

Abstract

Alternative splicing is a crucial mechanism of gene expression regulation that enormously increases the coding potential of our genome and represents an intermediate step between messenger RNA (mRNA) transcription and protein posttranslational modifications. Alternative splicing occupies a central position in the development and functions of the nervous system. Therefore, its deregulation frequently leads to several neurological human disorders. In the present review, we provide an updated overview on the impact of alternative splicing in Parkinson's disease (PD), the second most common neurodegenerative disorder worldwide. We will describe the alternative splicing of major PD-linked genes by collecting the current evidences about this intricate and not carefully explored aspect. Assessing the role of this mechanism on PD pathobiology may represent a central step toward an improved understanding of this complex disease.

Keywords: Alternative splicing; PD genes; Parkinson’s disease; Protein isoforms; mRNA splice transcripts.

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Figures

Fig. 1

Fig. 1

The alternative splicing mechanism. a Four main conserved DNA sequence motifs allow the splicing mechanism: the donor splice site GU (_5_′ SS), the acceptor splice site AG (_3_′ SS), the lariat branch point (A) located upstream of the acceptor site and the polypyrimidine tract (PPT) placed between the acceptor site and the branch point. The splicing machinery includes mainly five spliceosomal uridine-rich small nuclear ribonucleoproteins (snRNPs) (U1, U2, U4, U5, and U6) and further auxiliary RNA binding proteins. During the first step of spliceosome assembly, U1 snRNP base pairs with the 5′ splice site of the pre-mRNA (E complex), whereas U2 base pairs with the branch point (A complex). Then the tri-snRNP complex U4, U5, and U6 associates with the forming spliceosome (B complex), and both U1 and U4 are ejected. This allows U6 to replace U1 at the 5′ splice site (C complex) and leads to a U6–U2 interaction that gets close together the 5′ splice site and the branch point, allowing for a transesterification step. At the end, U5 brings near the two exons, joining them through a second transesterification reaction. b Five major alternative splicing events are currently known: exon skipping/inclusion, use of alternative 3′ splice site, use of alternative 5′ splice site, mutually exclusive exons, and intron retention. In blue, are represented the constitutive exons. Yellow and red represent the alternatively spliced exons. The splicing events rely on the interplay between the constitutive splicing motifs, the splicing regulatory sequences, the RNA secondary structures, the components of the spliceosome, and further auxiliary RNA-binding proteins. However, how the spliceosome decides which exons to include remains currently not clear

Fig. 2

Fig. 2

Structures of the alternative splicing variants of human dominant PD genes. Structures of the described mRNA splicing variants are represented in the figure as reported in Ensembl library (

http://www.ensembl.org/index.html

). On the left, each variant is indicated with a number corresponding to that indicated in Table 1. LRRK2 gene is illustrated in 5′-3′ sense, while SNCA and VPS35 genes are illustrated in antisense corresponding to their 3′-5′ sense transcription

Fig. 3

Fig. 3

Structures of the alternative splicing variants of human recessive PD genes. Structures of the described mRNA splicing variants are represented in the figure as reported in Ensembl library (

http://www.ensembl.org/index.html

). On the left, each variant is indicated with a number corresponding to that indicated in Table 2. All transcripts are illustrated in 5′-3′ sense, except PARK2, ATP13A2, and PLA2G6 genes, which are illustrated in antisense corresponding to their 3′–5′ sense transcription

Fig. 4

Fig. 4

Structures of the alternative splicing variants of human X-linked PD genes. Structures of the described mRNA splicing variants are represented in the figure as reported in Ensembl library (

http://www.ensembl.org/index.html

). On the left, each variant is indicated with a number corresponding to that indicated in Table 3. All transcripts are illustrated in 5′-3′ sense

Fig. 5

Fig. 5

Structures of the alternative splicing variants of the other human PD-related genes. Structures of the described mRNA splicing variants are represented in the figure as reported in Ensembl library (

http://www.ensembl.org/index.html

). On the left, each variant is indicated with a number corresponding to that indicated in Table 4. All transcripts are illustrated in 5′-3′ sense, except _MAO_-B and GBA genes, which are illustrated in antisense corresponding to their 3′-5′ sense transcription

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