Athena Andreadis, Ph.D.


Athena Andreadis, Ph.D.
Associate Professor
Faculty Appointment(s) and Affiliations:
School of Medicine
Cell Biology
Graduate School of Biomedical Sciences
Cell Biology Graduate Program
Neuroscience Graduate Program

Research interests

Our genes define us as a species, but our neuronal synapses define us as individuals. Normal brain development is a complex process that requires the coordinated expression of many genes. Understanding this regulation is prerequisite to elucidating the genetic causes of abnormal brain development. I examine alternative splicing, a gene regulatory mechanism vital for the proper functioning of the entire organism, and the nervous system in particular. Alternative splicing, which occurs in 90% of human genes, results in the production of multiple variants from a single gene and is a major contributor to proteomic complexity.

My chosen model is the human tau gene, whose product is instrumental in the function of the axon. Via alternative splicing, tau gives rise to multiple products that control axonal morphology and stability. Disturbances in tau splicing result in disruption of the axon and formation of tau structures called neurofibrillary tangles. Dementia sufferers display these tangles which correlate with the severity of common developmental and degenerative neurological disorders, including Down syndrome and Alzheimer's disease. The second most common dementia after Alzheimer's, frontotemporal dementia with Parkinsonism, is directly caused by misregulations in tau alternative splicing. The disease is caused by wild-type proteins present in incorrect ratios -- a paradigm of a dosage error effect. Finally, tau also plays an important role in development: individuals with microdeletions or microduplications of the tau locus suffer from developmental delay and learning disabilities, and tau null mice display learning disabilities and muscle defects.

This type of research may not only give us insights into how to predict, ameliorate or cure dementia, but also forms part of the bottom-up approach in answering one of the major questions both within and beyond science: how the brain creates a mind (the Binding Problem).

Landmark/significant papers

Andreadis A, Brown WM, Kosik KS. Structure and novel exons of the human tau gene. Biochemistry 1992; 31: 10626-10633.

Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Che LK, Norton J, Morris JC, Reed LA, Trojanowski J, Basun H, Lannfelt L, Neystat M, Fahn S, Dark F, Tannenberg T, Dodd P, Hayward N, Kwok JBJ, Schofield PR, Andreadis A, Snowden J, Craufurd D, Neary D, Owen F, Oostra BA, Hardy J, Goate A, van Swieten J, Mann D, Lynch T, Heutink P. Association of missense and 5' splice site mutations in tau with the inherited dementia FTDP-17. Nature 1998; 393:702-705.

Luo M-H, Leski M, Andreadis A. Tau isoforms which contain the domain encoded by exon 6 and their role in neurite elongation. J. Cell. Biochem. 2004, 91:880-895.

Luo M-H, Tse S-W, Memmott J, Andreadis A. Novel isoforms of tau that lack the microtubule-binding domain. J. Neurochem. 2004, 90:340-51.

Wang Y, Wang J, Gao L, Lafyatis R, Stamm S, Andreadis A. Tau exons 2 and 10, which are misregulated in neurodegenerative diseases, are partly regulated by silencers which bind a SRp30c / SRp55 complex that either recruits or antagonizes htra2beta1. J. Biol. Chem. 2005, 280:14230-14239.

Gao L, Tse SW, Conrad C, Andreadis A. Saitohin, which is nested in the tau locus and confers allele-specific susceptibility to several neurodegenerative diseases, interacts with Peroxiredoxin 6. J. Biol. Chem. 2005, 280:39268-72.

Gao L, Wang J, Wang Y, Andreadis A. SR protein 9G8 modulates splicing of tau exon 10 via its proximal downstream intron, a clustering region for frontotemporal dementia mutations. Mol. Cell. Neurosci. 2007, 34:48-58.

Wang Y, Gao L, Tse S-W, Andreadis A. Heterogeneous nuclear ribonucleoprotein E3 modestly activates splicing of tau exon 10 via its proximal downstream intron, a hotspot for frontotemporal dementia mutations. Gene 2010, 451:23-31.

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