Athena Andreadis PHD
Title Associate Professor
Institution University of Massachusetts Medical School
Department Cell and Developmental Biology
Address University of Massachusetts Medical School
55 Lake Avenue North
Worcester MA 01655
Telephone 508-856-1414
Email
Other Positions
Institution UMMS - Graduate School of Biomedical Sciences
Department Cell Biology

Institution UMMS - Graduate School of Biomedical Sciences
Department Neuroscience
Narrative

Cell Biology Department Website

Academic Background

BA, Harvard University, 1977
PhD. Massachusetts Institute of Technology, 1984

Current Appointments: UMass Medical School

Associate Professor of Cell Biology

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.

 

Schematic Representation of tau mRNA series

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

 

Publications
1. Andreadis A. Tau splicing and the intricacies of dementia. J Cell Physiol. 2012 Mar; 227(3):1220-5.
  View in: PubMed
 
2. Sumanasekera C, Kelemen O, Beullens M, Aubol BE, Adams JA, Sunkara M, Morris A, Bollen M, Andreadis A, Stamm S. C6 pyridinium ceramide influences alternative pre-mRNA splicing by inhibiting protein phosphatase-1. Nucleic Acids Res. 2012 May 1; 40(9):4025-39.
  View in: PubMed
 
3. Wang Y, Gao L, Conrad CG, Andreadis A. Saitohin, which is nested within the tau gene, interacts with tau and Abl and its human-specific allele influences Abl phosphorylation. J Cell Biochem. 2011 Nov; 112(11):3482-8.
  View in: PubMed
 
4. Kanaan NM, Morfini G, Pigino G, Lapointe NE, Andreadis A, Song Y, Leitman E, Binder LI, Brady ST. Phosphorylation in the amino terminus of tau prevents inhibition of anterograde axonal transport. Neurobiol Aging. 2012 Apr; 33(4):826.e15-30.
  View in: PubMed
 
5. Kanaan NM, Morfini GA, LaPointe NE, Pigino GF, Patterson KR, Song Y, Andreadis A, Fu Y, Brady ST, Binder LI. Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases. J Neurosci. 2011 Jul 6; 31(27):9858-68.
  View in: PubMed
 
6. Wang Y, Wang J, Gao L, Stamm S, Andreadis A. An SRp75/hnRNPG complex interacting with hnRNPE2 regulates the 5' splice site of tau exon 10, whose misregulation causes frontotemporal dementia. Gene. 2011 Oct 10; 485(2):130-8.
  View in: PubMed
 
7. Andreadis A. The tempting illusion of genetic virtue. Politics Life Sci. 2010 Mar; 29(1):76-8.
  View in: PubMed
 
8. Benderska N, Becker K, Girault JA, Becker CM, Andreadis A, Stamm S. DARPP-32 binds to tra2-beta1 and influences alternative splicing. Biochim Biophys Acta. 2010 May-Jun; 1799(5-6):448-53.
  View in: PubMed
 
9. Lapointe NE, Horowitz PM, Guillozet-Bongaarts AL, Silva A, Andreadis A, Binder LI. Tau 6D and 6P isoforms inhibit polymerization of full-length tau in vitro. Biochemistry. 2009 Dec 29; 48(51):12290-7.
  View in: PubMed
 
10. Wang Y, Gao L, Tse SW, 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 Feb 1; 451(1-2):23-31.
  View in: PubMed
 
11. Andreadis AA, Samson MC, Szomstein S, Newman MI. Epidermal inclusion cyst of the umbilicus following abdominoplasty. Plast Surg Nurs. 2007 Oct-Dec; 27(4):202-5.
  View in: PubMed
 
12. 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 Jan; 34(1):48-58.
  View in: PubMed
 
13. Wang J, Tse SW, Andreadis A. Tau exon 6 is regulated by an intricate interplay of trans factors and cis elements, including multiple branch points. J Neurochem. 2007 Jan; 100(2):437-45.
  View in: PubMed
 
14. Antonakoudis H, Kifnidis K, Andreadis A, Fluda E, Konti Z, Papagianis N, Stamou H, Anastasopoulou E, Antonakoudis G, Poulimenos L. Cardiac rehabilitation effects on quality of life in patients after acute myocardial infarction. Hippokratia. 2006 Oct; 10(4):176-81.
  View in: PubMed
 
15. Leroy O, Dhaenens CM, Schraen-Maschke S, Belarbi K, Delacourte A, Andreadis A, Sablonnière B, Buée L, Sergeant N, Caillet-Boudin ML. ETR-3 represses Tau exons 2/3 inclusion, a splicing event abnormally enhanced in myotonic dystrophy type I. J Neurosci Res. 2006 Sep; 84(4):852-9.
  View in: PubMed
 
16. Qiang L, Yu W, Andreadis A, Luo M, Baas PW. Tau protects microtubules in the axon from severing by katanin. J Neurosci. 2006 Mar 22; 26(12):3120-9.
  View in: PubMed
 
17. Andreadis A. Misregulation of tau alternative splicing in neurodegeneration and dementia. Prog Mol Subcell Biol. 2006; 44:89-107.
  View in: PubMed
 
18. Leroy O, Wang J, Maurage CA, Parent M, Cooper T, Buée L, Sergeant N, Andreadis A, Caillet-Boudin ML. Brain-specific change in alternative splicing of Tau exon 6 in myotonic dystrophy type 1. Biochim Biophys Acta. 2006 Apr; 1762(4):460-7.
  View in: PubMed
 
19. Glatz DC, Rujescu D, Tang Y, Berendt FJ, Hartmann AM, Faltraco F, Rosenberg C, Hulette C, Jellinger K, Hampel H, Riederer P, Möller 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 Feb; 96(3):635-44.
  View in: PubMed
 
20. Nishinaga H, Takahashi-Niki K, Taira T, Andreadis A, Iguchi-Ariga SM, Ariga H. Expression profiles of genes in DJ-1-knockdown and L 166 P DJ-1 mutant cells. Neurosci Lett. 2005 Dec 16; 390(1):54-9.
  View in: PubMed
 
21. Tse SW, Broderick JA, Wei ML, Luo MH, 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 Oct 10; 359:63-72.
  View in: PubMed
 
22. 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 Nov 25; 280(47):39268-72.
  View in: PubMed
 
23. 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 Apr 8; 280(14):14230-9.
  View in: PubMed
 
24. Andreadis A. Tau gene alternative splicing: expression patterns, regulation and modulation of function in normal brain and neurodegenerative diseases. Biochim Biophys Acta. 2005 Jan 3; 1739(2-3):91-103.
  View in: PubMed
 
25. Gao L, Tucker KL, Andreadis A. Transcriptional regulation of the mouse microtubule-associated protein tau. Biochim Biophys Acta. 2005 Jan 11; 1681(2-3):175-81.
  View in: PubMed
 
26. Luo MH, Tse SW, Memmott J, Andreadis A. Novel isoforms of tau that lack the microtubule-binding domain. J Neurochem. 2004 Jul; 90(2):340-51.
  View in: PubMed
 
27. Broderick J, Wang J, Andreadis A. Heterogeneous nuclear ribonucleoprotein E2 binds to tau exon 10 and moderately activates its splicing. Gene. 2004 Apr 28; 331:107-14.
  View in: PubMed
 
28. Luo MH, Leski ML, Andreadis A. Tau isoforms which contain the domain encoded by exon 6 and their role in neurite elongation. J Cell Biochem. 2004 Apr 1; 91(5):880-95.
  View in: PubMed
 
29. Lee G, Thangavel R, Sharma VM, Litersky JM, Bhaskar K, Fang SM, Do LH, Andreadis A, Van Hoesen G, Ksiezak-Reding H. Phosphorylation of tau by fyn: implications for Alzheimer's disease. J Neurosci. 2004 Mar 3; 24(9):2304-12.
  View in: PubMed
 
30. 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. 2004 Mar; 88(5):1078-90.
  View in: PubMed
 
31. Li K, Arikan MC, Andreadis A. Modulation of the membrane-binding domain of tau protein: splicing regulation of exon 2. Brain Res Mol Brain Res. 2003 Aug 19; 116(1-2):94-105.
  View in: PubMed
 
32. Andreadis AA, Hazen SL, Comhair SA, Erzurum SC. Oxidative and nitrosative events in asthma. Free Radic Biol Med. 2003 Aug 1; 35(3):213-25.
  View in: PubMed
 
33. Rao MV, Engle LJ, Mohan PS, Yuan A, Qiu D, Cataldo A, Hassinger L, Jacobsen S, Lee VM, Andreadis A, Julien JP, Bridgman PC, Nixon RA. Myosin Va binding to neurofilaments is essential for correct myosin Va distribution and transport and neurofilament density. J Cell Biol. 2002 Oct 28; 159(2):279-90.
  View in: PubMed
 
34. Higuchi M, Ishihara T, Zhang B, Hong M, Andreadis A, Trojanowski J, Lee VM. Transgenic mouse model of tauopathies with glial pathology and nervous system degeneration. Neuron. 2002 Aug 1; 35(3):433-46.
  View in: PubMed
 
35. Arikan MC, Memmott J, Broderick JA, Lafyatis R, Screaton G, Stamm S, Andreadis A. Modulation of the membrane-binding projection domain of tau protein: splicing regulation of exon 3. Brain Res Mol Brain Res. 2002 May 30; 101(1-2):109-21.
  View in: PubMed
 
36. Hartmann AM, Rujescu D, Giannakouros T, Nikolakaki E, Goedert M, Mandelkow EM, Gao QS, Andreadis A, Stamm S. Regulation of alternative splicing of human tau exon 10 by phosphorylation of splicing factors. Mol Cell Neurosci. 2001 Jul; 18(1):80-90.
  View in: PubMed
 
37. Stoss O, Olbrich M, Hartmann AM, Konig H, Memmott J, Andreadis A, Stamm S. The STAR/GSG family protein rSLM-2 regulates the selection of alternative splice sites. J Biol Chem. 2001 Mar 23; 276(12):8665-73.
  View in: PubMed
 
38. Mathews PM, Cataldo AM, Kao BH, Rudnicki AG, Qin X, Yang JL, Jiang Y, Picciano M, Hulette C, Lippa CF, Bird TD, Nochlin D, Walter J, Haass C, Lévesque L, Fraser PE, Andreadis A, Nixon RA. Brain expression of presenilins in sporadic and early-onset, familial Alzheimer's disease. Mol Med. 2000 Oct; 6(10):878-91.
  View in: PubMed
 
39. Wei ML, Memmott J, Screaton G, Andreadis A. The splicing determinants of a regulated exon in the axonal MAP tau reside within the exon and in its upstream intron. Brain Res Mol Brain Res. 2000 Sep 15; 80(2):207-18.
  View in: PubMed
 
40. Li H, Wagner E, McCaffery P, Smith D, Andreadis A, Dräger UC. A retinoic acid synthesizing enzyme in ventral retina and telencephalon of the embryonic mouse. Mech Dev. 2000 Jul; 95(1-2):283-9.
  View in: PubMed
 
41. 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. 2000 Feb; 74(2):490-500.
  View in: PubMed
 
42. Lilius L, Froelich Fabre S, Basun H, Forsell C, Axelman K, Mattila K, Andreadis A, Viitanen M, Winblad B, Fratiglioni L, Lannfelt L. Tau gene polymorphisms and apolipoprotein E epsilon4 may interact to increase risk for Alzheimer's disease. Neurosci Lett. 1999 Dec 17; 277(1):29-32.
  View in: PubMed
 
43. 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 VM, Reed L, Trojanowski JQ, Zhukareva V, Bird T, Schellenberg G, Wilhelmsen KC. 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 U S A. 1998 Oct 27; 95(22):13103-7.
  View in: PubMed
 
44. Conrad C, Amano N, Andreadis A, Xia Y, Namekataf K, Oyama F, Ikeda K, Wakabayashi K, Takahashi H, Thal LJ, Katzman R, Shackelford DA, Matsushita M, Masliah E, Sawa A. Differences in a dinucleotide repeat polymorphism in the tau gene between Caucasian and Japanese populations: implication for progressive supranuclear palsy. Neurosci Lett. 1998 Jul 3; 250(2):135-7.
  View in: PubMed
 
45. 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 PR, Hayward N, Kwok JB, 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 Jun 18; 393(6686):702-5.
  View in: PubMed
 
46. Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L, Andreadis A, Wiederholt WC, Raskind M, Schellenberg GD. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol. 1998 Jun; 43(6):815-25.
  View in: PubMed
 
47. Wei ML, Andreadis A. Splicing of a regulated exon reveals additional complexity in the axonal microtubule-associated protein tau. J Neurochem. 1998 Apr; 70(4):1346-56.
  View in: PubMed
 
48. Baker M, Kwok JB, Kucera S, Crook R, Farrer M, Houlden H, Isaacs A, Lincoln S, Onstead L, Hardy J, Wittenberg L, Dodd P, Webb S, Hayward N, Tannenberg T, Andreadis A, Hallupp M, Schofield P, Dark F, Hutton M. Localization of frontotemporal dementia with parkinsonism in an Australian kindred to chromosome 17q21-22. Ann Neurol. 1997 Nov; 42(5):794-8.
  View in: PubMed
 
49. Froelich S, Basun H, Forsell C, Lilius L, Axelman K, Andreadis A, Lannfelt L. Mapping of a disease locus for familial rapidly progressive frontotemporal dementia to chromosome 17q12-21. Am J Med Genet. 1997 Jul 25; 74(4):380-5.
  View in: PubMed
 
50. Conrad C, Andreadis A, Trojanowski JQ, Dickson DW, Kang D, Chen X, Wiederholt W, Hansen L, Masliah E, Thal LJ, Katzman R, Xia Y, Saitoh T. Genetic evidence for the involvement of tau in progressive supranuclear palsy. Ann Neurol. 1997 Feb; 41(2):277-81.
  View in: PubMed
 
51. Andreadis A, Wagner BK, Broderick JA, Kosik KS. A tau promoter region without neuronal specificity. J Neurochem. 1996 Jun; 66(6):2257-63.
  View in: PubMed
 
52. Andreadis A, Broderick JA, Kosik KS. Relative exon affinities and suboptimal splice site signals lead to non-equivalence of two cassette exons. Nucleic Acids Res. 1995 Sep 11; 23(17):3585-93.
  View in: PubMed
 
53. Andreadis A, Nisson PE, Kosik KS, Watkins PC. The exon trapping assay partly discriminates against alternatively spliced exons. Nucleic Acids Res. 1993 May 11; 21(9):2217-21.
  View in: PubMed
 
54. Andreadis A, Brown WM, Kosik KS. Structure and novel exons of the human tau gene. Biochemistry. 1992 Nov 3; 31(43):10626-33.
  View in: PubMed
 
55. Andreadis A, Rosenthal ER. The nucleotide sequence of leuB from Salmonella typhimurium. Biochim Biophys Acta. 1992 Jan 6; 1129(2):228-30.
  View in: PubMed
 
56. Taubman MB, Smith CW, Izumo S, Grant JW, Endo T, Andreadis A, Nadal-Ginard B. The expression of sarcomeric muscle-specific contractile protein genes in BC3H1 cells: BC3H1 cells resemble skeletal myoblasts that are defective for commitment to terminal differentiation. J Cell Biol. 1989 May; 108(5):1799-806.
  View in: PubMed
 
57. Andreadis A, Gallego ME, Nadal-Ginard B. Generation of protein isoform diversity by alternative splicing: mechanistic and biological implications. Annu Rev Cell Biol. 1987; 3:207-42.
  View in: PubMed
 
58. Breitbart RE, Andreadis A, Nadal-Ginard B. Alternative splicing: a ubiquitous mechanism for the generation of multiple protein isoforms from single genes. Annu Rev Biochem. 1987; 56:467-95.
  View in: PubMed
 
59. Andreadis A, Hsu YP, Hermodson M, Kohlhaw G, Schimmel P. Yeast LEU2. Repression of mRNA levels by leucine and primary structure of the gene product. J Biol Chem. 1984 Jul 10; 259(13):8059-62.
  View in: PubMed
 
60. Andreadis A, Hsu YP, Kohlhaw GB, Schimmel P. Nucleotide sequence of yeast LEU2 shows 5'-noncoding region has sequences cognate to leucine. Cell. 1982 Dec; 31(2 Pt 1):319-25.
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61. HITCHCOCK E, ANDREADIS A. SUBDURAL EMPYEMA: A REVIEW OF 29 CASES. J Neurol Neurosurg Psychiatry. 1964 Oct; 27:422-34.
  View in: PubMed
 
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Keyword
Last Name
Institution
    
 
 
 
Keywords   
tau Proteins
Exons
Alternative Splicing
RNA Splicing
Dementia
See all (314) keywords
Co-Authors  
McCaffery, Peter
Rudnicki, Anna
See all (2) people
Physical Neighbors  
Schwarting, Gerald
Crandall, James
Keller, Jeanne
Montecino, Martin
Gagliardi, Susan

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