Gopal Thinakaran

Professor

Department of Neurobiology

The University of Chicago
947 E. 58th St., MC0926
Chicago, IL 60637 

Email: gopal@uchicago.edu
Phone: (773) 834-3752
Office: JFK R212/Knapp Center

Thinakaran lab website

 

Research Summary

Cellular and molecular biology of Alzheimer's disease

 

Research Statement

Alzheimer’s disease (AD) is the major cause of dementia in the elderly and the sixth leading cause of death in the United States. This devastating disorder for which no cure is presently available strikes someone in the United States every 66 seconds. More than half the population over 80 years of age suffers from AD. The number of Americans living with AD at present is estimated at 5.3 million. As the lifespan of humans continues to increase in industrialized societies and emerging economies, AD is becoming an ever-increasing social burden for the health care system and emotional burden for the immediate family members.

A little over one hundred years ago, Alois Alzheimer, a German psychiatrist and neuropathologist, first presented the case study of a patient who suffered from the devastating illness that now bears his name. In a paper published in 1907, Alzheimer wrote: "Scattered through the entire cortex, especially in the upper layers, one found miliary foci that were caused by the deposition of a peculiar substance." Eighty years later, the "peculiar substance" was characterized as ~38-42 amino acid-long beta-amyloid peptides (Aß), which are derived from a larger type I transmembrane protein, termed amyloid precursor protein (APP). Cerebral deposition of Aß peptides in senile plaques is causally linked to AD. It is well established that Aß is associated with neuronal death and consequent memory loss.

The overarching goal of my research is to develop a better understanding of the molecular and cellular mechanisms that regulate Aß production. Specifically, my lab has been investigating the cell biology of two proteases, termed BACE1 and gamma-secretase, which sequentially cleave APP to generate Aß. BACE1 is a type I transmembrane aspartyl protease, whereas gamma-secretase is a multiprotein transmembrane complex made of the catalytic subunit presenilin (PS1 or PS2) and three other integral subunits: nicastrin, APH-1, and PEN-2. We use cultured neuronal and non-neuronal cell lines, primary neurons, knock-out mice and transgenic mouse models of AD pathogenesis in our investigations.

In recent years, we have investigated the amyloidogenic processing of APP in cholesterol- and sphingolipid-rich membrane microdomains, termed lipid rafts. Ongoing investigations focus on: 1) the role of S-palmitoylation on BACE1 and gamma-secretase microdomain localization and trafficking in cultured neurons and in mouse brain; 2) advanced live cell imaging of BACE1 trafficking and transport; 3) understanding how risk factors identified by GWAS studies modify AD pathogenesis. In addition, we have been interested in the physiological functions of Stanniocalcin 2, a protein whose expression is induced by the cellular adaptive response to protein misfolding stress, termed the unfolded protein response. We have recently uncovered a molecular function for Stanniocalcin 2 in cellular calcium homeostasis and are now exploring the potential involvement of calcium homeostasis in Alzheimer’s disease pathogenesis using cell culture and animal models.

 

Select Publications

De Rossi P, Buggia-Prévot V, Clayton BLL, Vasquez JB, van Sanford C, Andrew RJ, Lesnick R, Botté A, Deyts C, Salem S, Rao E, Rice RC, Parent A, Kar S, Popko B, Pytel P, Estus S, and Thinakaran G: Predominant expression of Alzheimer's disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts. Mol. Neurodegener. 2016, 11:59. PDF

Buggia-Prévot V and Thinakaran G: Significance of transcytosis in Alzheimer’s disease: BACE1 takes the scenic route to axons. Bioessays. 37:888-98, 2015. PDF

Buggia-Prévot V, Fernandez CG, Riordan S, Vetrivel KS, Roseman J, Waters J, Bindokas VP, Vassar R, and Thinakaran G: Axonal BACE1 dynamics and targeting in hippocampal neurons: a role for Rab11 GTPase. Molecular Neurodegeneration 9(1):1, 2014. PDF

Buggia-Prévot V, Fernandez CG, Udayar V, Vetrivel KS, Elie A, Roseman J, Sasse VA, Lefkow M, Meckler X, Bhattacharyya S, George M, Kar S, Bindokas VP, Parent AT, Rajendran L, Band H, Vassar R and Thinakaran G: A Function for EHD Family Proteins in Unidirectional Retrograde Dendritic Transport of BACE1 and Alzheimer's Disease Aβ production. Cell Reports 5:1552–1563, 2013. PDF

Zeiger W, Vetrivel KS, Buggia-Prévot V, Nguyen PH, Wagner SL, Villereal M and Thinakaran G: Ca2+ influx through store-operated Ca2+ channels reduces Alzheimer’s Disease β-amyloid peptide secretion. J. Biol. Chem. 288: 26955–26966, 2013.

Deyts C, Vetrivel KS, Shepherd YM, Dupré DJ, Thinakaran G and Parent AT: Novel Gαs-protein signaling associated with membrane-tethered APP intracellular domain. J. Neurosci. 32:1714-1729, 2012.

Gong P, Roseman J, Fernandez CG, Vetrivel KS, Bindokas VP, Zitzow LA, Kar S, Parent AT, and Thinakaran G: Transgenic neuronal overexpression reveals that stringently regulated p23 expression is critical for coordinated movement in mice. Mol Neurodegener. 6:87, 2011.

Zeiger W, Ito D, Swetlik C, Oh-hora M, Villereal ML, and Thinakaran G: Stanniocalcin 2 is a negative modulator of store-operated calcium entry. Mol. Cell Biol. 18: 3710-22, 2011.

Vetrivel KS, Barman A, Chen Y, Nguyen PD, Wagner SL, Prabhakar R, and Thinakaran G: Loss of cleavage at β’-site contributes to the apparent increase of Aβ secretion by BACE1-GPI processing of APP. J. Biol. Chem. 286: 26166–26177, 2011.

Meckler X, Roseman, J, Das P, Cheng H, Pei S, Keat M, Kassarjian B, Golde TE, Parent AT, and Thinakaran G: Reduced Alzheimer’s disease ?-amyloid deposition in transgenic mice expressing S-palmitoylation-deficient APH1aL and nicastrin. J. Neurosci. 30: 16160-16169, 2010.

Chen H, Vetrivel KS, Drisdel R, Li T, Carter M, Gong P, Chen Y, Nguyen PD, Placania L, Li Y-M, Wong PC, Green WN, Kounnas MZ and Thinakaran G: S-palmitoylation of gamma-secretase subunits. J. Biol. Chem. 284:1373-1384, 2009.

Vetrivel KS, Cheng H, Kim SH, Chen Y, Barnes NY, Parent AT, Sisodia SS and Thinakaran G: Spatial segregation of gamma-secretase and substrates in distinct membrane domains. J. Biol. Chem. 280:25892-25900, 2005.

Ito D, Walker JR, Thompson CS, Moroz I, Lin W, Veselits ML, Hakim AM, Fienberg AA, and Thinakaran G: Characterization of stanniocalcin 2, a novel target of the mammalian unfolded protein response with cytoprotective properties. Mol. Cell. Biol. 24:9456-69, 2004.

Vetrivel KS, Cheng H, Sakurai T, Li T, Nukina N, Wong PC, and Thinakaran G: Association of gamma-secretase complex with lipid raft microdomains in post-Golgi and endosomes membranes. J. Biol. Chem. 279:44945-44954, 2004.

Sato N, Urano F, Leem J-Y, Kim SH, Donoviel D, Bernstein A, Li M, Lee AS, Ron D, Veselits ML, Sisodia SS and Thinakaran G: Upregulation of BiP and CHOP by the unfolded protein response is independent of presenilin expression. Nature Cell Biol. 2:863-870, 2000.