 |
Appointments:
Associate Professor
Department of Neurobiology
Committee on Molecular Medicine/MPMM
Committee on Cellular and Molecular
Physiology
Committee on Neurobiology
|
Education:
Ph.D., University of Guelph,
Canada 1992
M.S., Madurai Kamaraj University
Madurai,
India 1987
B.A., Madurai Kamaraj
University
Madurai, India 1985
|
Contact:
Phone: (773) 834-3752
Fax: (773)
702-5790
E-Mail:
gopal@uchicago.edu
Address:
The University of Chicago
Knapp Center, JFK R212
924 East 57th Street
Chicago, Illinois 60637
|
Related Research Interests:
|
|
Gopal Thinakaran, Ph.D.
Cellular and Molecular Biology of Alzheimer's Disease
Research Summary
For
the past several years, my research efforts have been directed towards
understanding the molecular events that underly the pathogenesis of
Alzheimer’s disease (AD). AD, a progressive
neurodegenerative disorder, is the most common cause of dementia in the
elderly, effecting ~7 - 10% of individuals over 65 years of age.
The prevalence of this disease increases to 40% in persons over 80
years of age. Approximately 5 - 10 % of AD, classified as
early-onset familial AD (FAD) (age of onset < 60 years), is
inherited in an autosomal dominant manner and in some of these
pedigrees, mutations in genes encoding the amyloid precursor protein
(APP), presenilin 1(PS1) and presenilin 2 (PS2) cosegregate with
FAD. Mutations in PS1/PS2 account for the majority of the cases
of FAD.
Pathological lesions called senile plaques found in the brains of AD
patients contain extracellular deposits of 40-42 amino acid-long
peptides, termed b-amyloid (Ab). Aβ holds a central
position in AD pathogenesis; it is generated by sequential
endoproteolytic processing of amyloid precursor protein (APP) by BACE
and γ-secretase. BACE is a transmembrane aspartyl
protease and γ-secretase is a multiprotein complex
containing presenilin 1 (PS1) or presenilin 2 (PS2), nicastrin, APH-1
and PEN-2. FAD-linked APP and PS1 variants enhance the production
of highly amyloidogenic Ab42 peptides. The precise mechanisms
involved in g-secretase cleavage of APP, and the manner in which
FAD-linked mutations favor the production of Ab42 remain unclear.
There has been considerable epidemiological interest in the
relationship between cholesterol and susceptibility to AD. We are
particularly interested in the cell biology of g-secretase and
amyloidogenic processing of APP in cholesterol- and sphingolipid-rich
membrane microdomains, termed lipid rafts. In addition, we are
also investigating the role of presenilins in synaptic function using
cell biology, electrophysiology, and live imaging strategies. Our
goal is to uncover information critical for the development of rational
therapeutic strategies for the treatment of AD.
Neuronal Stress Response
In diseases such as triplet disorders, and prion diseases, mutations in
specific genes lead to misfolding of the encoded protein products and
other cellular proteins. Thus, regardless of the etiology,
several neurodegenerative diseases are characterized by the
accumulation of misfolded proteins within the secretory pathway,
cytoplasm or nucleus, and the association between protein aggregation
and neurodegenerative diseases is an emerging field of study. My
lab is interested in protein folding stress within the secretory
pathway. We are investigating the ER stress-related gene
expression with the aim of identifying common features involved in
hypoxic and ischemic neuronal damage, aging, and
neurodegeneration. These investigations utilize a variety of cell
culture systems and well-characterized transgenic mouse models of
FAD. Our goal is to characterize the cellular and molecular
cascade of early events that lead to the etiopathogenesis of AD and
other neurodegenerative disorders.
Selected Papers
Sato, N., Urano, F.,
Yoon Leem, J., Kim, S.H., Li, M., Donoviel, D., Bernstein, A., Lee,
A.S., Ron, D., Veselits, M.L., Sisodia, S.S. and Thinakaran, G.
Upregulation of BiP and CHOP by the unfolded-protein response is
independent of presenilin expression. Nat. Cell Biol.,
212:863-70, 2000.
Leem, J.Y., Vijayan, S., Han, P., Cai, D., Machura, M., Lopes, K.O.,
Veselits, M.L., Xu, H. and Thinakaran, G. Presenilin 1 is required for
maturation and cell surface accumulation of nicastrin. J. Biol. Chem.,
277:19236-40, 2002.
Leem, J-Y., Saura, C.A., Pietrzik, C., Christianson, J., Wanamaker, C.,
King, L.T., Veselits, M.L., Tomita, T., Gasparini, L. Iwatsubo, T., Xu,
H., Green, W., Koo, E.H., and Thinakaran, G. A role for
presenilin 1 in regulating the delivery of amyloid precursor protein to
the cell surface. Neurobiol. Dis., 11:64-82, 2002.
Takasugi, N., Tomita, T., Tsuruoka, M., Hayashi, I., Takahashi, Y.,
Thinakaran, G., and Iwatsubo, T. Differential Roles of Presenilin
Cofactors in the Formation and Function of γ-Secretase
Complex. Nature, 422:438-441, 2003.
Thinakaran, G. and Parent, A.T. Identification of the role of
presenilins beyond Alzheimer's disease. Pharmacol. Res., 50:411-418,
2004.
Ito, D., Walker, J.R., Thompson, C.S., Moroz, I., Lin, W., Veselits,
M.L., Hakim, A.M., Fienberg, A.A., 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, K.S., Cheng, H., Sakurai, T., Li, T., Nukina, N., Wong, P.C.,
and Thinakaran, G. Association of γ-secretase complex with
lipid raft microdomains in post-Golgi and endosomes membranes. J. Biol.
Chem., 279: 44945-44954, 2004.
Parent, A.T., Barnes, N.Y., Taniguchi, Y., Thinakaran, G., and Sisodia,
S.S. Presenilin attenuates receptor-mediated signaling and synaptic
function. J. Neurosci., 25: 1540-1549, 2005.
Vetrivel, K.S., Cheng, H., Kim, S.H., Chen, Y., Barnes, N.Y., Parent,
A.T., Sisodia, S.S. and Thinakaran, G. Spatial segregation of
g-secretase and substrates in distinct membrane domains. J. Biol.
Chem., 280:25892-25900, 2005.
Thinakaran, G. and Sisodia, S.S. Presenilins and Alzheimer Disease: the
Ca2+ conspiracy. News and Views. Nat. Neurosci., 9:1354-5, 2006.
Vetrivel, K.S., Zhang, Y.W., Xu, H. and Thinakaran, G. Pathological and
physiological functions of presenilins. Mol. Neurodegener., 1:4, 2006.
Vetrivel, K.S. and Thinakaran, G. Amyloidogenic processing of
β-amyloid precursor protein in intracellular compartments.
Neurology, 66(2 Suppl 1):S69-73, 2006.
Vetrivel, K.S., Gong, P., Bowen, J.W., Cheng, H., Chen, Y., Carter, M.,
Nguyen, P.D., Placanica, L., Wieland, F.T., Li, Y.M., Kounnas, M.Z. and
Thinakaran, G. Dual roles of the transmembrane protein p23/TMP21 in the
modulation of amyloid precursor protein metabolism. Mol. Neurodegener.,
2:4, 2007.
Cheng, H., Vetrivel, K.S., Gong, P., Meckler, X., Parent, A.T., and
Thinakaran, G. Mechanisms of Disease: new therapeutic strategies for
Alzheimer's diseases targeting amyloid precursor protein processing in
lipid rafts. Nature Clinical Practice Neurology, 3:374-82, 2007.
|
