Expertise:
Cell
and Molecular Biology
Alzheimer’s Disease:
AD is the most common cause of dementia in the elderly.
This progressive neurodegenerative disorder affects ~10%
of individuals over 65 years of age and ~40% of persons over
80 years of age. At present approximately 4 million Americans
are effected by AD. With the increasing life expectancy,
it is predicted that this estimate will more than double
by the year 2030 in the U.S. alone and account for 20 million
patients worldwide, making AD one of the major health problems
facing this nation and the world.
I) Amyloidogenic processing of APP: 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 (A b ). A b holds a central position in
AD pathogenesis; it is generated by sequential endoproteolytic
processing of amyloid precursor protein (APP) by BACE and
g -secretase. BACE is a transmembrane aspartyl protease and
g -secretase is a multiprotein complex containing presenilin
1 or 2 (PS1or PS2), nicastrin, APH-1 and PEN-2. Mutations
in genes encoding APP, PS1 and PS2 cosegregate
with FAD, and enhance the production of highly amyloidogenic
A b 42 peptides. We are using a combination of biochemical
and subcellular fractionation and immunofluorescence localization
strategies to unravel the subcellular and membrane microdomain
organization of APP secretases and investigate amyloidogenic
processing of APP and A b 40 and A b 42 production.
II) The role of PS1 in synaptic structure
and function: Mounting evidence indicates that synaptic
structures are the initial targets for AD, and memory deficits
are mainly due to synaptic dysfunction in the earliest
clinical stages of the disease. In addition to its role
in A b production, PS1 also regulates other cellular functions
such as protein trafficking, cellular calcium homeostasis,
glutamatergic synaptic transmission etc. Interaction with
select proteins such as b -catenin and cadherins play a
role in the latter aspects of PS1 biology. Using PS1 knock
out mice and transgenic mice expressing deletion mutants
of PS1, we are testing the hypothesis that PS1- b -catenin/cadherin
interaction(s) are critical for neuronal development during
embryogenesis, and for the development of neuropathology
in AD, i.e. A b deposition and alternations in synaptic
structure and function. These studies utilize cell biology,
electrophysiology, and live imaging strategies.
Biology of neuronal stress response:
In many neurodegenerative diseases such as AD, polyglutamine
triplet disorders, Parkinson’s disease, 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 specifically interested
in protein folding stress within the secretory pathway. We
are investigating the endoplasmic reticulum stress-related
gene expression to identify common features involved in hypoxic
and ischemic neuronal damage, aging, and neurodegeneration.
These investigations utilize a variety of cell culture systems
(to experimentally perturb protein folding) and well-characterized
transgenic mouse and Drosophila models of neurodegenerative
diseases (such as AD, Parkinson’s disease).
Laboratory personnel:
Dr. Angèle Parent, Ph.D., Research Associate (Associate
Professor)
aparent@uchicago.edu
Dr. Vetrivel Subramaniam, Ph.D., Postdoctoral Fellow
vetrivel@uchicago.edu
Dr. Li Liu, M.D., Ph.D., Postdoctoral Fellow
liliu@bsd.uchicago.edu
Dr. Haipeng Cheng, Ph.D., Postdoctoral Fellow
hcheng@bsd.uchicago.edu
Dr. Ping Gong, Ph.D., Postdoctoral Fellow
gong_ping@hotmail.com
Dr. Jinhu Guo, Ph.D., Postdoctoral Fellow
jguo@bsd.uchicago.edu
Jim Bowen, Predoctoral Student
bowen@uchicago.edu |
