Interests
The aim of my research is to study the cellular and molecular pathways involved in the pathogenesis of Alzheimer’s disease (AD). More specifically, my focus is to understand how G protein-coupled receptors (GPCRs) and β-arrestins regulate the amyloid pathway, synaptic plasticity and cognition, and to determine how to therapeutically modulate GPCR/β-arrestin-biased signaling in AD and other neurological disorders. I hypothesize that the β-arrestins provide a putative basis to understand the link between GPCRs and Aβ generation through regulation of the γ-secretase complex and will provide insight into the pathophysiology of GPCR dysfunction in AD and a novel therapeutic avenue for intervention in AD. Consequently, I have adopted two approaches to address my research questions: (1) a focused approach aimed at understanding the molecular, cellular and physiological role of GPR3 and β-arrestin 2 in synaptic function and cognition and regulation of γ-secretase activity, Aβ accumulation and Aβ-mediated synaptotoxicity and (2) a broad approach aimed at attaining a more extensive understanding of the GPCR/β-arrestin network in the brain and in regulation of Aβ generation and the γ-secretase complex under physiological and pathophysiological conditions. By integrating mouse genetics with cellular and biochemical techniques, electrophysiology and behavioral studies, and optogenetic tools, I hope to achieve a greater understanding of the mechanism(s) regulating GPCR and β-arrestin synaptic function and cognition in AD.
Training
| B.Sc. | Biology | Baylor University | 1998 |
| Ph.D. | Cell Biology | University of Texas Health Science Center | 2004 |
| Postdoctoral Fellow | Neuroscience | KU Leuven/VIB Center for the Biology of Disease | 2009 |
Positions Held
| Staff Scientist | KU Leuven/VIB Center for the Biology of Disease | 2009-2015 |
| Assistant Professor | KU Leuven | 2012-2015 |
| Assistant Professor | University of Pittsburgh School of Medicine | 2016-present |
Honors and awards
2011 Cornelli Young Investigator Award for research in Alzheimer’s Disease
2011 Memory Loss in Alzheimer’s Disease (MEMOSAD) Award
Selected Publications
Huang Y, Rafael Guimarães T, Todd N, Ferguson C, Weiss KM, Stauffer FR, McDermott B, Hurtle BT, Saito T, Saido TC, MacDonald ML, Homanics GE, Thathiah A. G protein-biased GPR3 signaling ameliorates amyloid pathology in a preclinical Alzheimer's disease mouse model. Proc Natl Acad Sci U S A. 2022 Oct 4;119(40):e2204828119. doi: 10.1073/pnas.2204828119. Epub 2022 Sep 26. PMID: 36161942; PMCID: PMC9546571.
Todd NK, Huang Y, Lee JY, Doruker P, Krieger JM, Salisbury R, MacDonald M, Bahar I, Thathiah A. GPCR kinases generate an APH1A phosphorylation barcode to regulate amyloid-β generation. Cell Rep. 2022 Jul 19;40(3):111110. doi: 10.1016/j.celrep.2022.111110. PMID: 35858570; PMCID: PMC9373432.
Welty S, Thathiah A, Levine AS. DNA Damage Increases Secreted Aβ40 and Aβ42 in Neuronal Progenitor Cells: Relevance to Alzheimer's Disease. J Alzheimers Dis. 2022;88(1):177-190. doi: 10.3233/JAD-220030. PMID: 35570488; PMCID: PMC9277680.
Guimarães TR, Swanson E, Kofler J, Thathiah A. G protein-coupled receptor kinases are associated with Alzheimer's disease pathology. Neuropathol Appl Neurobiol. 2021 Dec;47(7):942-957. doi: 10.1111/nan.12742. Epub 2021 Jul 19. PMID: 34164834; PMCID: PMC8735815.
Thathiah A. β-Arrestin2 arrests the clearance of tau in FTLD. Proc Natl Acad Sci U S A. 2020 Mar 31;117(13):6968-6970. doi: 10.1073/pnas.2001455117. Epub 2020 Mar 18. PMID: 32188777; PMCID: PMC7132289.
Mann JR, Gleixner AM, Mauna JC, Gomes E, DeChellis-Marks MR, Needham PG, Copley KE, Hurtle B, Portz B, Pyles NJ, Guo L, Calder CB, Wills ZP, Pandey UB, Kofler JK, Brodsky JL, Thathiah A, Shorter J, Donnelly CJ. RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43. Neuron. 2019 Apr 17;102(2):321-338.e8. doi: 10.1016/j.neuron.2019.01.048. Epub 2019 Feb 27. PMID: 30826182; PMCID: PMC6472983.
Welty S, Teng Y, Liang Z, Zhao W, Sanders LH, Greenamyre JT, Rubio ME, Thathiah A, Kodali R, Wetzel R, Levine AS, Lan L. RAD52 is required for RNA-templated recombination repair in post-mitotic neurons. J Biol Chem. 2018 Jan 26;293(4):1353-1362. doi: 10.1074/jbc.M117.808402. Epub 2017 Dec 7. PMID: 29217771; PMCID: PMC5787811.
Huang Y, Todd N, Thathiah A. The role of GPCRs in neurodegenerative diseases: avenues for therapeutic intervention. Curr Opin Pharmacol. 2017 Feb;32:96-110. doi: 10.1016/j.coph.2017.02.001. Epub 2017 Mar 10. PMID: 28288370.
Guix FX, Sannerud R, Berditchevski F, Arranz AM, Horré K, Snellinx A, Thathiah A, Saido T, Saito T, Rajesh S, Overduin M, Kumar-Singh S, Radaelli E, Corthout N, Colombelli J, Tosi S, Munck S, Salas IH, Annaert W, De Strooper B. Tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments. Mol Neurodegener. 2017 Mar 10;12(1):25. doi: 10.1186/s13024-017-0165-0. PMID: 28279219; PMCID: PMC5345265.
Huang Y, Skwarek-Maruszewska A, Horré K, Vandewyer E, Wolfs L, Snellinx A, Saito T, Radaelli E, Corthout N, Colombelli J, Lo AC, Van Aerschot L, Callaerts-Vegh Z, Trabzuni D, Bossers K, Verhaagen J, Ryten M, Munck S, D'Hooge R, Swaab DF, Hardy J, Saido TC, De Strooper B, Thathiah A. Loss of GPR3 reduces the amyloid plaque burden and improves memory in Alzheimer's disease mouse models. Sci Transl Med. 2015 Oct 14;7(309):309ra164. doi: 10.1126/scitranslmed.aab3492. PMID: 26468326.
Huang Y, Thathiah A. Regulation of neuronal communication by G protein-coupled receptors. FEBS Lett. 2015 Jun 22;589(14):1607-19. doi: 10.1016/j.febslet.2015.05.007. Epub 2015 May 14. PMID: 25980603.
Thathiah A, Spittaels K, Hoffmann M, Staes M, Cohen A, Horré K, Vanbrabant M, Coun F, Baekelandt V, Delacourte A, Fischer DF, Pollet D, De Strooper B, Merchiers P. The orphan G protein-coupled receptor 3 modulates amyloid-beta peptide generation in neurons. Science. 2009 Feb 13;323(5916):946-51. doi: 10.1126/science.1160649. PMID: 19213921.