Biomedical subjects

Debra Toiber

Publications and source records attributed to Debra Toiber.

4 recordsLinked to original sources

PubMed2006

Modulated splicing-associated gene expression in P19 cells expressing distinct acetylcholinesterase splice variants.

Alternative splicing configurations and acetylcholinesterase (AChE) gene expression are both modified in neurons under stress. However, it is unclear if these phenomena are functionally interrelated. Using a home-made spotted microarray focused on splicing-associated transcripts, we tested the effects of excess 3' splice variants of human AChE on splicing-related gene expression in semi-differentiated neuronal P19 cells. Of the tested transcripts, 17.3% and 20.2% showed modified expression levels (log2 of the ratio<-0.3 or>0.3) in transfected P19 cells overexpressing the stress-inducible AChE-R variant or the synaptic AChE-S protein, respectively. Multiple transcripts encoding serine-arginine rich (SR) and SR-related splicing regulators were suppressed in cells expressing either of these variants, whereas the gene groups including splicing-related helicases and transcripts involved in apoptosis displayed variant-specific changes. Our findings are compatible with the assumption that both neuronal overexpression and alternative splicing of pre-AChE mRNA may be causally involved in initiating global changes in neuronal alternative splicing, causing subsequent modifications in the expression patterns of numerous target genes.

Acetylcholinesterase↗

PubMed2004

Function of alternative splicing.

Alternative splicing is one of the most important mechanisms to generate a large number of mRNA and protein isoforms from the surprisingly low number of human genes. Unlike promoter activity, which primarily regulates the amount of transcripts, alternative splicing changes the structure of transcripts and their encoded proteins. Together with nonsense-mediated decay (NMD), at least 25% of all alternative exons are predicted to regulate transcript abundance. Molecular analyses during the last decade demonstrate that alternative splicing determines the binding properties, intracellular localization, enzymatic activity, protein stability and posttranslational modifications of a large number of proteins. The magnitude of the effects range from a complete loss of function or acquisition of a new function to very subtle modulations, which are observed in the majority of cases reported. Alternative splicing factors regulate multiple pre-mRNAs and recent identification of physiological targets shows that a specific splicing factor regulates pre-mRNAs with coherent biological functions. Therefore, evidence is now accumulating that alternative splicing coordinates physiologically meaningful changes in protein isoform expression and is a key mechanism to generate the complex proteome of multicellular organisms.

Alternative Splicing↗

PubMed2004

Combinatorial complexity of 5' alternative acetylcholinesterase transcripts and protein products.

To explore the scope and significance of alternate promoter usage and its putative inter-relationship to alternative splicing, we searched expression sequence tags for the 5' region of acetylcholinesterase (ACHE) genes. Three and five novel first exons were identified in human and mouse ACHE genes, respectively. Reverse transcription-PCR and in situ hybridization validated most of the predicted transcripts, and sequence analyses of the corresponding genomic DNA regions suggest evolutionarily conserved promoters for each of the novel exons identified. Distinct tissue specificity and stress-related expression patterns of these exons predict combinatorial complexity with known 3' alternative AChE mRNA transcripts. Unexpectedly one of the 5' exons encodes an extended N terminus in-frame with the known AChE sequence, extending the increased complexity to the protein level. The resultant membrane variant(s), designated N-AChE, is developmentally regulated in human brain neurons and blood mononuclear cells. Alternative promoter usage combined with alternative splicing may thus lead to stress-dependent combinatorial complexity of AChE mRNA transcripts and their protein products.

5' Untranslated Regions↗

PubMedDate not supplied

Cellular stress reactions as putative cholinergic links in Alzheimer's disease.

Alzheimer's disease involves normal cellular aging and chronic cellular stress events, leading to interrelated changes in gene expression and subsequent neurodegeneration. Premature death of cholinergic neurons and the formation of amyloid fibrils separately initiated the cholinergic and amyloid hypotheses of Alzheimer's disease. Here, we present evidence to the fact that these two distinct phenomena both associate with specific changes in acetylcholinesterase (AChE) gene expression within cholinergic neurons. For example, calcium misregulation promotes aberrant transcription and pro-apoptotic events, as well as AChE-induced modifications in cellular signal cascades. These reciprocally intercept with AChE regulation at the Endoplasmic Reticulum, modifying AChE gene expression, folding and signaling. Altered AChE properties may reflect changes in the enzymatic and/or non-enzymatic features of the multiple AChE splice variants. Under chronic cellular stress, aberrant AChE regulation may thus facilitate apoptotic pathways, promoting plaque formation, cognitive impairments and degeneration of cholinergic nerve cells.

Acetylcholinesterase↗