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Srp20 regulates TrkB pre‐mRNA splicing to generate TrkB‐Shc transcripts with implications for Alzheimer’s disease
Author(s) -
Wong Jenny,
Garner Brett,
Halliday Glenda M.,
Kwok John B. J.
Publication year - 2012
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2012.07873.x
Subject(s) - tropomyosin receptor kinase b , minigene , biology , alternative splicing , exon , microbiology and biotechnology , gene knockdown , gene , genetics , neurotrophic factors , receptor
Previously, we reported elevated levels of the neuron‐specific tropomyosin receptor kinase B (TrkB) transcript, TrkB‐ sarc homology containing (Shc) in the hippocampus of Alzheimer’s disease (AD) brains. In this study, we determined how TrkB‐Shc transcripts are increased in AD. Utilizing a TrkB minigene transiently transfected into SHSY5Y cells, we found increased exon 19 inclusion in TrkB minigene transcripts (to generate TrkB‐Shc) following cellular exposure to amyloid beta 1–42 (Αβ 42 ). As this suggested altered TrkB pre‐mRNA splicing in AD, we conducted an in silico screening for putative splice regulatory protein‐binding sites in the intron/exon splice regulatory regions of exons 18 and 19 of the TrkB gene and then assessed their gene expression profiles using a microarray database of control/AD post‐mortem human hippocampal brain tissue. We found significant changes in serine/arginine protein 20 (Srp20) gene expression in AD cases and confirmed this using a second cohort of control/AD. In vitro , we found increased Srp20 mRNA levels in SHSY5Y cells treated with Αβ 42 fibrils. Moreover, Srp20 over‐expression was found to increase exon 19 inclusion in TrkB minigene transcripts and ratio of endogenous TrkB‐Shc:TrkB‐TK+ mRNA expression. Conversely, Srp20 expression knockdown produced the opposite effects. Our findings suggest that dysregulation of factors regulating TrkB pre‐mRNA splicing may contribute to gene expression changes that occur in AD.