Aberrant Alternative Splicing Events in Parkinson's Disease

Abstract

Alternative splicing (AS) using a sole gene to express multiple transcripts with diverse protein coding sequences and/or RNA regulatory elements raises genomic complexities. In the nervous system, several thousand AS events play important roles in ion transportation, receptor recognition, neurotransmission, memory, and learning. Not surprisingly, AS influences human physiology, development, and disease. Many research studies have focused on aberrant AS in nervous system diseases, including Parkinson's disease (PD), the second most common progressive neurodegenerative disorder of the central nervous system. PD affects the lives of several million people globally. It is caused by protein aggregation, such as in Lewy bodies, and the loss of dopaminecontaining neurons in the substantia nigra of the midbrain. To our knowledge, six genes, including PARK2, SNCAIP, LRRK2, SNCA, SRRM2, and MAPT, are involved in aberrant AS events in PD patients. In this review, we highlight the relevance of aberrant AS in PD and discuss the use of an aberrant AS profile as a potential diagnostic or prognostic marker for PD and as a possible means of applying therapy.

Finding a possible biomarker to tackle Parkinson’s disease by splice analysis and random point mutations to counter the expression of genes involved in Parkinson’s disease

“…They found a noteworthy upregulation of the upstream (5) exons of SRRM2 and a downregulation of the downstream exons, which caused downregulation of the long isoform. (Fu et al, 2013). Thus, we targeted these genes and tried to counter their regulation to restore original gene expression.…”

“…(Fu et al, 2013) Thus, mutations were carried out on Exon 9 of SNCAIP gene to decrease the expression of exon 9. Various mutations were carried out (insertions, deletions, substitutions, indels and duplications) with an aim to find silencer motifs which could silence the expression of SNCAIP.…”

Alternative RNA Splicing in the Pathogenesis of GBM

“…Dysregulation of splicing has been associated with several human diseases including spinal muscular atrophy, Alzheimer's disease, and Parkinson's disease , Glatz et al 2006, Fu et al 2013, and its connection with cancer, resulting in the activation of oncogenes or inactivation of tumor suppressors, has been well established [reviewed in (Oltean and Bates 2014, Zhang and Manley 2013, David and Manley 2010]. For example, the splicing factor SF2/ASF, up-regulated in a variety of cancer types, acts as a proto-oncogene by affecting the alternative splicing of BIN1, S6K1 and MNK2.…”

“…The activity of splicing factors and SREs is contextdependent with the most frequent form of alternative splicing being expression of a cassette exon (exon skipping). Other alternative splicing modes include mutual exclusivity, use of alternative 3' or 5' splice sites, alternate transcriptional start sites, and intron retention [ Figure 1, (Tazi, Bakkour, and Stamm 2009)].Dysregulation of splicing has been associated with several human diseases including spinal muscular atrophy, Alzheimer's disease, and Parkinson's disease , Glatz et al 2006, Fu et al 2013, and its connection with cancer, resulting in the activation of oncogenes or inactivation of tumor suppressors, has been well established [reviewed in (Oltean and Bates 2014, Zhang and Manley 2013, David and Manley 2010]. For example, the splicing factor SF2/ASF, up-regulated…”

Alternative Splicing in CKD

“…There are .2000 splicing mutation disease entities known, resulting in 370 diseases and involving 303 genes. 6 The disease most commonly linked to deregulation of AS is cancer, [7][8][9] however, AS has also been implicated in diseases ranging from Parkinson 10 to dilated cardiomyopathy 11 or diabetes. 12,13 An increasing number of splice isoforms have been recently reported to be associated with various CKDs.…”