Cdk5 regulates the phosphorylation of tyrosine 1472 NR2B and the surface expression of NMDA receptors

Tau aggregation is one of the major features in Alzheimer's disease and in several other tauopathies, including frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), and progressive supranuclear palsy (PSP). More than 35 mutations in the tau gene have been identified from FTDP-17 patients. A group of these mutations alters splicing of exon 10, resulting in an increase in exon 10 inclusion into tau mRNA. Abnormal splicing with inclusion of exon 10 into tau mRNA has also been observed in PSP and AD patients. These results indicate that abnormal splicing of exon 10, leading to the production of tau with exon 10, is probably one of the mechanisms by which tau accumulates and aggregates in tauopathic brains. Therefore, modulation of exon 10 splicing in the tau gene could potentially be targeted to prevent tauopathies. To identify small molecules or compounds that could potentially be developed into drugs to treat tauopathies, we established a cell-based high-throughput screening assay. In this review, we will discuss how realistic, specific biological molecules can be found to regulate exon 10 splicing in the tau gene for potential treatment of tauopathies. Alternative splicing of exon 10 in the tau gene Splicing of pre-mRNA is a complicated process that is regulated by intron and exon sequences, SR (serine/argininerich) proteins, and other non-SR splicing factors, for example, heterogeneous nuclear ribonucleoproteins (hnRNPs). Alternative splicing occurs when the introns of a certain pre-mRNA are excised in more than one way, producing structurally and functionally different proteins from the same gene in different cells, or different developmental stages. It is estimated that more than 60% of human genes undergo alternative splicing, making the cellular process an essential mechanism for generating protein diversity [1-4]. Both constitutive and alternative splicing play important roles in the regulation of gene expression in eukaryotes [5]. A growing number of genetic diseases have been found to be caused by alternative or aberrant splicing events [6-9]. Mutations in cis-elements for splicing are primarily responsible for these diseases. However, tissue-specific splicing factors, such as those identified in amyotrophic lateral sclerosis (ALS), are also suggested to cause the aberrant pathogenic processing of pre-mRNA [10-13]. In addition, polymorphisms and from 8th International Conference on Alzheimer's Disease Drug Discovery New York, NY, USA. 15–16 October 2007 Published: 3 December 2008 BMC Neuroscience 2008, 9(Suppl 2):S10 doi:10.1186/1471-2202-9-S2-S10 <supplement> <title> <p>Proceedings of the 8<sup>th </sup>International Conference on Alzheimer's Disease Drug Discovery</p> </title> <editor>Howard Fillit</editor> <sponsor> <note>The publication of this supplement was made possible by the generous support of the conference sponsors: Forest Laboratories, Inc.; Bellus Health Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; Esai, Inc., Ortho-McNeil Neurologics, Inc.; Sanofi-Aventis US, Inc.; Schering-Plough; Accera, Inc.; Acumen Pharmaceuticals, Inc.; Pfizer Inc.; and Wyeth Research. </note> </sponsor> <note>Reviews</note> <url>http:// www.biomedcentral. com/content/pdf/1471-2202-9-S2-info.pdf</url> </supplement> This article is available from: http://www.biomedcentral. com/1471-2202/9/S2/S10 © 2008 Zhou et al; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. BMC Neuroscience 2008, 9(Suppl 2):S10 http://www.biomedcentral. com/1471-2202/9/S2/S10