Amantha Thathiah, PhD

  • Assistant Professor, Neurobiology

Phone

412-383-4078

E-mail

amantha@pitt.edu

Location

6062 BST3

Research Interest Summary

Cellular and molecular pathogenesis in Alzheimer's disease.

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.

 

Mann JR, et al. Rna Binding Antoagonizes neurotoxic phase transitions of TDP-43. Neuron. 2019; 102 321-338 e328.

 

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. United States; 2018; 293: 1353–62. doi: 10.1074/jbc.M117.808402.

 

Yunhong Huang, Nicholas Todd, Amantha Thathiah, The role of GPCRs in neurodegenerative diseases: avenues for therapeutic intervention, Current Opinion in Pharmacology, Volume 32, 2017, Pages 96-110, ISSN 1471-4892, https://doi.org/10.1016/j.coph.2017.02.001.

 

Guix, F.X., Sannerud, R., Berditchevski, F. et al. Tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments. Mol Neurodegeneration 12, 25 (2017). https://doi.org/10.1186/s13024-017-0165-0

 

Huang Y, Thathiah A. Regulation of neuronal communication by G protein-coupled receptors. FEBS Lett. 2015 Jun 22;589(14):1607-19.

 

Thathiah A, Horré K, Snellinx A, Vandewyer E, Huang Y, Ciesielska M, De Kloe G, Munck S, De Strooper B.  β-arrestin 2 regulates Aβ generation and γ-secretase activity in Alzheimer's disease. Nat Med. 2013 Jan;19(1):43-9.

 

Thathiah A, De Strooper B. The role of G protein-coupled receptors in the pathology of Alzheimer's disease. Nat Rev Neurosci. 2011 Feb;12(2):73-87.

 

Thathiah A, De Strooper B. G protein-coupled receptors, cholinergic dysfunction, and Abeta toxicity in Alzheimer's disease. Sci Signal. 2009 Oct 20;2(93):re8.

 

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.