Postdoctoral Position Available

Athena Andreadis, Ph.D.

Academic Role: Associate Professor

Faculty Appointment(s) In:
   Cell Biology

Other Affiliation(s):
   Program in Neuroscience

Genetic Causes of Abnormal Brain Development

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 70% of vertebrate 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 (the information transmitter for each neuron). Via the process of 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 pathological tau structures called neurofibrillary tangles. Dementia sufferers display these tangles which correlate with the severity of common developmental and degenerative neurological disorders (Alzheimer's disease, progressive supranuclear palsy, Pick's disease, corticobasal degeneration). 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.

My dissection of the tau system with molecular and cellular tools isbeginning to clarify the role of tau variants in neuronal morphology and fate,the identity and role of molecules that interact with tau protein and the mechanism of action of regulators which modulate the splicing of its gene. All these molecules almost certainly control nervous system function, and may eitherprevent or promote tangle formation. This research will give insights into 1)neuronal-specific splicing regulation, 2) the regulatory cascades within the normal brain and 3) the causes of dementia, with the long term view of preventing or curing neuronal loss. This type of research 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).

Ongoing Projects

• Regulation of Alternative Splicing in the Nervous System
• Functions of the Tau Protein beyond Microtubule Binding
• Function of the Primate-Specific Protein Saitohin
• The Role of Tau and Saitohin in Neurodegeneration

Representative Publications

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 J, Tse S-W, Andreadis A. Tau exon 6 is regulated by an intricate interplay of trans factors and cis elements, including multiple branch points.  J. Neurochem. 2007, 100:437-445.

Leroy O, Dhaenens C-M, Schraen-Maschke S, Belarbi K, Andreadis A, Cooper T, Sablonnière B, Buée L, Sergeant N, Caillet-Boudin M-L. Tau exon 2/3 inclusion is strongly repressed by ETR-3, a splicing event abnormally enhanced in myotonic dystrophy of type 1.  J. Neurosci. Res. 2006, 84:852-859

Glatz DC, Rujescu D, Tang Y, Berendt FJ, Hartmann AM, Faltraco F, Rosenberg C, Hulette C, Jellinger K, Hampel H, Rieder P, Moeller HJ, Andreadis A, Henkel K, Stamm S.  The alternative splicing of tau exon 10 and its regulatory proteins clk2 and tra2-beta1 changes in sporadic Alzheimer’s disease.  J. Neurochem. 2006, 96:635-44.
Andreadis, A. Misregulation of tau alternative splicing in neurodegeneration and dementia. Invited review.  P. Jeanteur, editor. Prog. Mol. Subcell. Biol. 2006, 44:89-107.

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.

Tse S-W, Broderick JA, Wei M-L, Luo M-H, Smith D, McCaffery P, Stamm S, Andreadis A.  Identification, expression analysis, genomic organization and cellular location of a novel protein with a RhoGEF domain.  Gene 2005, 359:63-72.

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, Tucker KL, Andreadis A.  Transcriptional regulation of the mouse microtubule-associated protein tau. Biochim. Biophys. Acta 2005, 1681:175-81.

Andreadis A. Tau gene alternative splicing: expression patterns, regulation and modulation of function in normal brain and neurodegenerative diseases. Invited review.  GS Bloom, ME King and LI Binder, editors. Biochim. Biophys. Acta 2005, 1739:91-103.

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

Wang J, Gao QS, Wang Y, Lafyatis R, Stamm S, Andreadis A. Tau exon 10, whose missplicing causes frontotemporal dementia, is regulated by an intricate interplay of cis elements and trans factors. J. Neurochem. 88:1078-90, 2004.

Lee G, Thangavel R, Sharma V, Litersky J, Bhaskar K, Fang S, Do L, Andreadis A, van Hoesen G, Ksiezak-Reding H. Phosphorylation of tau by fyn: implications for Alzheimer’s disease. J. Neurosci. 24:2304-12, 2004.

Luo M, Leski M, Andreadis A. Tau Isoforms which Contain the Domain Encoded by Exon 6 and their Role in Neurite Elongation. J. Cell. Biochem. 91:880-895, 2004.

Broderick J, Wang J, Andreadis A. Heterogeneous nuclear ribonucleoprotein E2 binds to tau exon 10 and moderately activates its splicing. Gene 331:107-114, 2004.

Li K, Arikan M, Andreadis A. Modulation of the membrane-binding projection domain of tau protein: splicing regulation of exon 2. Mol. Brain Res. 116:94-105, 2003.

Arikan M, Memmott J, Lafyatis R, Screaton G, Stamm S, Andreadis A. Modulation of the membrane-binding projection domain of tau protein: splicing regulation of exon 3. Mol. Br. Res. 101:109-21, 2002.

Higuchi M, Ishihara T, Zhang B, Hong M, Andreadis A, Trojanowski JQ, Lee VMY. Transgenic mouse model of tauopathies with glial pathology and nervous system degeneration. Neuron 35:433-46, 2002.

Hartmann AM, Rujescu D, Giannakouros T, Nikolakaki E, Goedert M, Mandelkow E, Gao Q-S, Andreadis A, Stamm S. Regulation of alternative splicing of human tau exon 10 by phosphorylation of splicing factors. Mol. Cell. Neurosci. 18:80-90, 2001.

Gao QS, Memmott J, Lafyatis R, Stamm S, Screaton G, Andreadis A. Complex regulation of tau exon 10, whose missplicing causes frontotemporal dementia. J. Neurochem. 74:490-500, 2000.

Li H, Wagner E, McCaffery P, Smith D, Andreadis A, Dräger U. A retinoic acid synthesizing enzyme in ventral retina and telencephalon of the embryonic mouse. Mech. Dev. 95:283-289, 2000.

Wei ML, Memmott J, Screaton, Andreadis A. The splicing determinants of a regulated exon in the axonal MAP tau reside within the exon and in its upstream intron. Mol. Br. Res. 80:207-218, 2000.

Stoss O, Olbrich M, Hartmann AM, Konig H, Memmott J, Andreadis A, Stamm S. The STAR/GCG family protein rSLM-2 regulates the selection of alternative splice sites. J. Biol. Chem. 276:8665-73, 2000.

Wei ML, Andreadis A. Splicing of a regulated exon reveals additional complexity in the axonal MAP tau. J. Neurochem. 70:1346-1356, 1998.

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 393:702-705, 1998.

Clark LN, Poorkaj P, Wszolek Z, Geschwind DH, Nasreddine ZS, Miller B, Li D, Payami H, Awert F, Markopoulou K, Andreadis A, D'Souza I, Lee VMY, Reed L, Trojanowski J, Zhukareva V, Bird T, Schellenberg G, Wilhelmsen K. Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17. Proc. Natl. Acad. Sci. USA 95:13103-13107,1998.

Andreadis A, Wagner B, Broderick JA, Kosik KS. A tau promoter region without neuronal specificity. J. Neurochem. 66:2257-2263, 1996.

Andreadis A, Broderick JA, Kosik KS. Relative exon affinities and suboptimal splice site signals lead to non-equivalence of two cassette exons. Nucl. Acids Res. 23:3585-3593, 1995.

Andreadis A, Nisson P, Kosik, KS, Watkins P. The exon trapping assay partly discriminates against alternatively spliced exons. Nucl. Acids Res. 21:2217-2221, 1993.

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

Book

Andreadis A. To Seek Out New Life: The Biology of Star Trek. New York: Crown Publishers Inc., 1998.

Rotation Project Background

Our research centers on tau, a protein which stabilizes the cytoskeleton of the neuronal axon. Tau has additional functions (for example, it also dictates microtubule spacing and hence axon caliber, and it also interacts with the axonal membrane, forming part of a signal cascade) and discharges them by producing variants via a molecular mechanism known as alternative splicing. Misregulation of tau splicing results in frontotemporal dementia with Parkinsonism, the second most common dementia after Alzheimer's. So our focus is dual: to discover 1) the mechanisms and factors which govern tau alternative splicing and 2) the additional functions and ligands of the tau protein.

Potential Rotation Projects

1. Analysis of novel ligands which interact with specific domains of the tau protein
2. Analysis of known splicing factors which regulate tau alternative splicing
3. Examination of the expression patterns of tau isoform variants in neuronal tissues at different developmental stages
4. Investigation of saitohin, a primate-specific gene nested in the tau locus that confers susceptibility to dementia

Techniques: cloning by various methods, directed mutagenesis, protein expression and purification in prokaryotic and eukaryotic systems, Westerns, Northerns, Northwesterns, PCR, RT-PCR, mammalian cell culture, transfections, in vitro binding and crosslinking assays, two- and three-hybrid systems (yeast and mammalian), co-immunoprecipitations, immunofluorescence, in situ hybridizations

Academic Background

Current Appointments: UMass Medical School

Associate Professor of Cell Biology

Office: S7-326
Phone: 508-856-1414
E-mail: Athena.Andreadis@umassmed.edu
Keywords: Neurobiology, Cytoskeleton, Gene Expression, Neurodegeneration, RNA Splicing

More on Athena Andreadis' Research Research | Publications | Rotations | Biography View All Sections on One Page

Postdoctoral Position Available A position is available immediately to study regulation of the mammalian nervous system at the molecular level. The research will focus on mechanisms and consequences of expressing isoforms of neuronal-specific genes that arise from alternative splicing. Candidates should have a Ph. D. with experience in molecular and cellular biology; knowledge of immunological techniques is strongly desirable. Please send C. V. and the names/phone numbers/email addresses of three references. For more details, please contact Dr. Andreadis. UMMS is an Affirmative Action/Equal Opportunity Employer.