Table of Contents
1. MSA Annual Patient Conference Rescheduled in Boston May 3 - 5, 2002
2. MSA Donations
3. Announcing the European Multiple System Atrophy Study Group
4. Boston Globe article on MSA
5. New fact sheet explaining Olivopontocerebellar atrophy (OPCA)
6. News from the Center for Neurodegenerative Disease Research
7. NIH Funded Studies involving Alpha-Synuclein (2002)
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
1. MSA Annual Patient Conference Rescheduled in Boston May 3 - 5, 2002
(Contributed by Don Summers donsums@shy-drager.com)
We're back on track for Boston!!!!!
The Boston Meeting for MSA Patients, Families & Researchers has been
re-scheduled for
May 3rd thru 5th, 2002
As initially scheduled, the meeting will take place at the Holiday Inn,
Logan Airport. Again, a block of rooms has been reserved in
the name of "THE SDS/MSA SUPPORT GROUP".
Reservations may be made by calling either the hotel direct
at 617-569-5250 or the Holiday Inn toll free number, 800-465-4329.
When requesting room reservations, please use the following
identifier code: 2SDS
The rooms are reserved at $129.00 per night. The facility is within a mile
of the airport and offers free shuttle service to and from the airport. Call
the Holiday Inn, Logan Airport from the free phone near the baggage claim
area. Handicapped rooms are available. Please inform the staff of
your special needs when you register and when you arrive.
GENERAL MEETING SCHEDULE
Friday, May 3rd
7:00 PM -- Registration and Social Hour
Saturday, May 4th
8:00 AM -- Buffet Breakfast
9:00 AM -- Meeting begins
12:00 Noon to 1:15 -- Lunch
1:15 to 5:00 -- Meetings Continue
Sunday, May 5th
9:00 AM to 10:00 AM -- Continental Breakfast
10:00 AM to 12:00 Noon -- Wrap-up session and general business meeting
(A detailed schedule will be available at registration.)
Dr. Roy Freeman of Beth Israel-Deaconess Medical Center will be our host
and has arranged for several guest speakers.
There is no cost for the meeting. Scheduled meals are provided by the
SDS/MSA Support Group. Your lodging, transportation and other meals are at
your expense.
Please e-mail me don.summers@shy-drager.com
if you plan to attend. In your e-mail please include the following:
1. Your name
2. Your home city
3. The number of people attending
This information is urgently needed to finalize food services!
Don Summers
President
SDS/MSA Support Group
1-866-SDS-4999
email: don.summers@shy-drager.com
website: http://www.shy-drager.com
-----------------------------------------
2. MSA Donations
These are two of the most popular options for MSA donations in the USA.
If you need suggestions for donations in other countries let me know.
a. The SDS/MSA Support Group
The SDS/MSA Support Group now has memorial envelopes
available. These envelopes are pre-printed with the
address of the Support Group and have a space inside
to enter the name of the person the gift is intended
to be allocated to. They are tastefully done and are
available in any number to survivors.
Please notify me if you wish to distribute these
envelopes at the memorial services for your loved
ones.
Don Summers
President, The SDS/MSA Support Group
email: Don.Summers@shy-drager.com
Toll free: 866-737-4999
The Shy-Drager Syndrome/Multiple System Atrophy
Support Group is a full non-profit organization
approved by the Internal Revenue Service.
Donations fund the entire operation of the Group.
Services include:
- a toll-free number to call for information and
physician referral
- the maintenance of the group website
http://www.shy-drager.com
- access to the Shydrager mail list
- an annual patient/caregiver/family member meeting
with prominent physicians.
Please visit the website at www.shy-drager.com
Don Summers can be reached at this toll-free number,
866-737-4999
Contributions of any amount may be mailed to:
The SDS/MSA Support Group
2004 Howard Lane
Austin, Texas 78728
b. Vanderbilt Shy-Drager Research Fund
Family members and friends of patients with Multiple
System Atrophy or Shy-Drager syndrome have
occasionally expressed an interest in making a
financial contribution that can be used for research
on this condition. Accordingly, we have established a
fund for this purpose. All gifts are very much
appreciated.
Donations for Multiple System Atrophy or Shy-Drager
syndrome research can be sent to:
Vanderbilt Shy-Drager Research Fund
Vanderbilt University Medical Center
AA-3228 Medical Center North
Nashville, TN 37232-2195
-----------------------------------------
3. Announcing the European Multiple System Atrophy Study Group - EMSA-SG
"Dear Pam,
With interest I read you mail about the MSA/SHY-Drager "online" support
group. This is just to inform you that there exists a European MSA Study
Group, initiated from the Department of Neurology, University of
Innsbruck (study coordinator: Prof. Werner Poewe, head of the Department
of Neurology, assistant coordinator: Prof. Gregor Wenning).
It would be of great help for us if you could inform your members,
especially those from Europe, about this initiative. More details you
can find on our homepage under
http://www.emsa-sg.org
In case you need more information please let us know.
Kindest regards and many thanks for your help in advance."
Ursula Knapp
EMSA-SG secretariat
Department of Neurology, University of Innsbruck
Head: Prof. Werner POEWE, MD
A-6020 Innsbruck, Anichstraße 35
Telefon: ++43/512/504-3850
Fax: ++43/512/504-3852
Email: werner.poewe@uibk.ac.at
gregor.wenning@uibk.ac.at
EMSA-SG Secretariat: ursula.knapp@uibk.ac.at
-----------------------------------------
4. Boston Globe article on MSA
(Contributed by Carol Langer cblanger@aol.com)
This appeared in the Boston Globe as a side bar in an article about brain
pacemakers. Tony Swartz-Lloyd is a member of the Boston area MSA
support group.
---
The Boston Globe
January 1, 2002
"For MSA Patients, Remedies Are Elusive"
By: Judy Foreman
Despite the promise of deep brain stimulation for a number of neurologic
problems, there are some conditions for which it doesn't seem to help,
including a baffling - and devastating - condition called multiple system
atrophy, or MSA, one of several diseases loosely termed "Parkinson's Plus."
MSA, a neurodegenerative disease that is often misdiagnosed as Parkinson's,
affects an estimated 25,000 to 100,000 people.
"It's like a thief in the night," said Tony Swartz-Lloyd, 65, a longtime
vice president at Beth Israel Deaconess Medical Center who is now retired
and coping with MSA. "It's a weird and elusive disease. . . . It takes
a
little piece of you here, a little piece there. You don't realize what's
missing at first."
MSA, for which there is no long-term effective treatment, often starts, like
Parkinson's, with a loss of dopamine-producing cells in the brain. But
unlike Parkinson's, dopamine-boosting drugs don't seem to help for more than
a couple of years.
Early symptoms of MSA include loss of balance and coordination, difficulty
speaking, a drop in blood pressure upon standing up but high blood pressure
while lying down, stiffness and slowness of movement. Patients often develop
other problems, such as impotence and difficulty urinating, that are
triggered by degeneration in the autonomic nervous system, which controls
involuntary bodily functions.
Despite the gloomy prognosis that many MSA patients face - gradual loss of
many bodily functions and death within six to eight years - there are some
bright spots, notably research suggesting that an underlying problem appears
to be abnormal deposits (on brain cells) of a protein called
alpha-synuclein.
Researchers are also studying neuroprotective drugs to keep brain cells from
dying in diseases such as MSA and Parkinson's, and other agents to help new
brain cells grow.
Copyright (c) 2002 Globe Newspaper Company
Record Number: 0201010293
-----------------------------------------
5. New fact sheet explaining Olivopontocerebellar atrophy (OPCA):
Finally they've rewritten this topic to include more up to date information.
Note that OPCA can fall under the heading of:
1. MSA - Multiple System Atrophy (sporadic/non-hereditary)
or
2. SCA - Spinocerebellar Ataxia (hereditary)
See: http://www.emedicine.com/neuro/topic282.htm
-----------------------------------------
6. News from the Center for Neurodegenerative Disease Research.
(Contributed by Steve Crawford bigdeebe@aol.com)
"Dear Mr. Crawford,
We have come a long way since the discovery of MSA and this has been driven
by exciting work in the last 4 years on the protein (known as
alpha-synuclein) that forms the toxic aggregates in brain cells of MSA
patients. These new insights into MSA are prerequisites for identifying
targets for novel drug discovery efforts for MSA patients, but this still
requires substantial investments in time and resources. However, I am
pleased to say Penn and our Center for Neurodegenerative Disease Research
(CNDR; with which Dr. Hurtig and his colleagues work very closely) is now a
leader in research on this subject, so you should know that many of us feel
we have turned an important corner on efforts to develop better therapies
for MSA. Please visit our CNDR website at the address below for more
information.
http://www.uphs.upenn.edu/cndr/
Finally, as an indication of our optimism about moving forward in
understanding MSA, I can tell you that we have a grant pending now that will
enable experts from across the USA to work together in multidisciplinary
studies of MSA and we are hopeful it will be funded in the near future
thereby enabling us to ramp our activities further in this area of
research."
Sincerely,
John Q. Trojanowski, M.D., Ph.D.
Center for Neurodegenerative Disease Research
Division of Anatomic Pathology
Department of Pathology and Laboratory Medicine
HUP, Maloney 3rd Floor
36th and Spruce Streets
Philadelphia, PA 19104-4283 USA
Tel: 215-662-6399; Fax: 215-349-5909
E-mail: trojanow@mail.med.upenn.edu
-----------------------------------------
7. National Institutes of Heath - Funded Studies involving Alpha-Synuclein
(2002)
These studies are all investigating possible treatments which might prevent
alpha-synuclein aggregation and thus have potential for Multiple System
Atrophy as well. See: https://www-commons.cit.nih.gov/crisp/
----
Grant Number: 5P01AG009215-12
PI Name: TROJANOWSKI, JOHN Q.
PI Email: trojanow@mail.med.upenn.edu
PI Title: LABORATORY MEDICINE
Project Title: MOLECULAR SUBSTRATES OF AGING AND NEURON DEATH
Abstract: Mechanisms of brain dysfunction and death due to neurodegenerative
diseases of the central nervous system (CNS) are poorly understood, but the
emergence of profound cognitive and/or motor impairments in these
heterogeneous diseases is a manifestation of the progressive and massive
degeneration of selectively vulnerable populations of neurons that
distinguishes neurodegenerative diseases from normal aging. Additionally,
intracellular filamentous inclusions are neuropathological hallmarks of many
neurodegenerative diseases despite their heterogeneity. For example,
abnormal alpha-synuclein filaments aggregate to form Lewy bodies (Lbs) in
neurons and they are signature lesions of Parkinson's disease (PD), dementia
with Lbs (DLB) and an Alzheimer's disease (AD) subtype known as the LB
variant of AD (LBVAD), while multiple system atrophy (MSA) is characterized
by glial cytoplasmic inclusions (GCIs) composed of alpha-synuclein filaments
aggregate to form Lewy bodies (Lbs) in neurons and they are signature
lesions of Parkinson's disease (PD), dementia with Lbs (DLB) and an
Alzheimer's disease (AD) subtype known as the LB variant of AD (LBVAD),
while multiple system atrophy (MSA) is characterized by glial cytoplasmic
inclusions (GCIs) composed of alpha-synuclein filaments. Although these
inclusions often were regarded as epiphenomena unrelated to mechanisms of
brain degeneration, this view has undergone dramatic revisions after the
discoveries that: mutations in the alpha- synuclein cause familial PD in
rare kindreds, alpha-synuclein is a major component of Lbs and GCIs, and
wild type, as well as mutant alpha- synuclein form filaments in vitro
similar to those in Lbs and GCIs. Moreover, the pressure or abundant
alpha-synuclein from filaments in vitro similar to those in Lbs and GCIs.
Moreover, the presence of abundant alpha-synuclein Lbs in the most common
variant of sporadic AD (i.e., LBVAD), >60% of familial AD brains and >50%
of
Down's syndrome brains with AD provides an opportunity to elucidate
mechanisms of the enigmatic, but frequent overlap of AD and PD. Finally, we
also have shown that beta- and gamma-synucleins accumulate in dystrophic
overlap of AD and PD. Finally, we also have shown that beta- and
gamma-synucleins accumulate in dystrophic hippocampal processes in PD and
DLB. Thus, we hypothesize that accumulations of synuclein filaments or
aggregates play a mechanistic role in neurodegenerative diseases
characterized by abundant synuclein pathology, and this Program Project
grant describes four complementary Projects to test this hypothesis with the
support of an Administrative,. Clinical, and Neuropathology Core. The
Projects are highly synergistic and pursue research conducted on disease
brains with authentic human synuclein pathology (Project 1), as well as on
mechanisms of synuclein pathologies using in vitro (Project 2), transgenic
fly (Project 3) and transgenic mouse (Project 4) models. This Program
Project will provide new insights into mechanisms of synuclein pathologies
and their role in brain degeneration, which are likely to accelerate efforts
to improve the diagnosis and therapy of these and other neurodegenerative
disorders characterized by filamentous brain lesions.
Thesaurus Terms:
Alzheimer's disease, Lewy body, Parkinson's disease, aging, alpha synuclein,
histopathology, molecular pathology, neural degeneration
Institution: UNIVERSITY OF PENNSYLVANIA
1 COLLEGE HALL
PHILADELPHIA, PA 19104
Fiscal Year: 2002
Department: PATHOLOGY AND LAB MEDICINE
Project Start: 01-AUG-1990
Project End: 30-APR-2005
ICD: NATIONAL INSTITUTE ON AGING
IRG: ZAG1
----
Grant Number: 1R43AG020031-01
PI Name: LEBOWITZ, MICHAEL S.
PI Email: msl@panaceapharma.com
PI Title:
Project Title: Alpha-Synuclein: A Drug Target for Parkinson's Disease
Abstract: DESCRIPTION (provided by applicant): Parkinson's disease (PD)
affects 1 percent of the population over 60 years of age and is one of the
most common motor disorders. A pathologic hallmark of PD is the deposition
of intracellular protein inclusions known as Lewy bodies in the neurons of
affected individuals. The protein alpha-synuclein is a primary component of
Lewy bodies and recent evidence has implicated alpha-synuclein
oligomerization as a key step in Lewy body formation and in PD
neuropathology. The ultimate goal of this work will be the development of
pharmaceuticals that can inhibit alpha-synuclein oligomerization and thus
Lewy body formation and neurodegeneration. In this phase I grant we will
identify and characterize peptide-based inhibitors of alpha-synuclein
oligomerization. We will study the alpha-synuclein and
alpha-synuclein-peptide interactions and identify the structure/activity
relationships involved in the peptide inhibition of alpha-synuclein
oligomerization. Finally, we will verify the plausibility of using
a-synuclein oligomerization inhibitors in a cell culture model of Lewy body
formation. This work will lay the foundation for a phase II grant in which
we will identify small molecule drug candidates that act as a-synuclein
oligomerization inhibitors, and begin pre-clinical testing of both the small
molecule and peptide-based drug candidates in animal models of Lewy body
disease. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE
Thesaurus Terms:
Lewy body, Parkinson's disease, alpha synuclein, antiparkinson drug, drug
design /synthesis /production cell aggregation, inhibitor /antagonist,
neural degeneration, protein protein interaction, protein structure function
Institution: PANACEA PHARMACEUTICALS, INC.
9700 GREAT SENECA HWY
ROCKVILLE, MD 20850
Fiscal Year: 2002
Department:
Project Start: 01-AUG-2001
Project End: 30-APR-2002
ICD: NATIONAL INSTITUTE ON AGING
IRG: ZRG1
----
Grant Number: 1R01AG018440-01A1
PI Name: MASLIAH, ELIEZER
PI Email: emasliah@ucsd.edu
PI Title: PROFESSOR
Project Title: B-Synuclein as a Treatment for Lewy Body Disease
Abstract: The new title of this revised application: "beta- synuclein
as a
treatment for Lewy body disease" reflects the modified and sharper focus
on
our scientific approach in response to the reviewers' major concern that
synuclein might be more relevant for understanding Lewy body disease (LBD).
We now propose a new concept where beta-synuclein, a naturally occurring
anti-aggregation molecule and non-amyloidogenic homologue of
alpha-synuclein, might prevent the neurotoxic effects of alpha- synuclein
and could be a suitable target for the development of an alternative
treatment for LBD. In this context, we propose the following Specific Aims:
1) To characterize the mechanisms by which beta-synuclein blocks
alpha-synuclein aggregation. We hypothesize that beta-synuclein may interact
with alpha-synuclein through specific beta-synuclein domains, leading to
inhibition of alpha-synuclein aggregation. To test this hypothesis, we will
study the effects of mutant recombinant beta-synucleins and synthetic
beta-synuclein derived peptides on alpha-synuclein aggregation, using
immunoblotting analysis, Congo red/Thioflavine-S staining, and electron
microscopy. Additional studies of synuclein binding will be performed by
immunoblotting with His-tagged alpha- and beta-synuclein 2) To determine if
the anti-aggregation effect of beta-synuclein is protective in neuronal cell
lines expressing alpha-synuclein. We hypothesize that beta-synuclein may be
neuroprotective by blocking alpha- synuclein aggregation. To test this
hypothesis, alpha-synuclein- overexpressing GT1-7 and B103 neuronal cells
will be co- transfected with beta-synuclein GT1-7 cells will be evaluated
for cell viability, mitochondrial function, oxidative stress conditions,
GnRH secretion, altered mitochondria morphology and inclusion body
formation. B103 cells will be evaluated by analysis of neurite formation and
cell adhesion. Immunoblotting experiments will be performed with cells
co-transfected with c- myc-tagged beta-synuclein to assess binding to
alpha-synuclein. To determine potential novel treatments, alpha-synuclein-
overexpressing GT1-7 and B103 cells will be treated with beta-
synuclein-expressing recombinant adeno-associated viral vector (rAAV). 3) To
determine if beta-synuclein blocks alpha-synuclein aggregation and
neurodegeneration in in vivo model systems of LBD. We hypothesize that
beta-synuclein may inhibit alpha- synuclein aggregation in vivo. To test
this hypothesis, we will cross alpha-synuclein tg mice with either beta-
synuclein tg or knockout mice where murine alpha- or beta-synuclein gene is
deleted. Mice will undergo detailed behavioral, neurochemical and
neuropathological examination to determine if beta-synuclein expression
affects the functional and structural alterations promoted by
alpha-synuclein and might act as a basis for treatment of LBD. To assess the
potential for treatment development, alpha-synuclein tg mice will be treated
with a beta- synuclein-expressing rAAV. In summary, we will utilize a
multi-system approach (a cell-free, cell culture and tg mouse systems) to
ascertain the anti- aggregation potential of beta-synuclein as a therapeutic
target for development of novel treatments for LBD.
Thesaurus Terms:
Lewy body, alpha synuclein, antitoxin, inhibitor /antagonist,
neuroprotectant, protein folding, protein structure function
axon, cell adhesion, cytotoxicity, dendrite, inclusion body, mutant, nervous
system disorder therapy, protein binding, protein protein interaction adeno
associated virus group, electron microscopy, gene targeting,
immunoprecipitation, laboratory mouse, staining, tissue /cell culture,
transfection /expression vector, transgenic animal, western blotting
Institution: UNIVERSITY OF CALIFORNIA SAN DIEGO
GILMAN & LA JOLLA VILLAGE DR
SAN DIEGO, CA 92093
Fiscal Year: 2002
Department: NEUROSCIENCES
Project Start: 01-SEP-2001
Project End: 31-AUG-2006
ICD: NATIONAL INSTITUTE ON AGING
IRG: ZRG1
----
Grant Number: 1R21NS043661-01
PI Name: MORGAN, DAVID G.
PI Email: dmorgan@hsd.usf.edu
PI Title:
Project Title: A vaccine approach to Parkinson's disease
Abstract: DESCRIPTION (provided by applicant) Recent work evaluating gene
defects leading to Parkinson's Disease (PD) suggests that accumulation of
alpha-synuclein may be a critical step in the pathogenic mechanisms leading
to Lewy body Parkinsonism. One of us (RM) has developed a rat model of
alpha-synuclein over-expression which results in long term elevations of
synuclein production and concomitant degeneration of tyrosine hydroxylase
neurons in substantia nigra. Because the model uses intracranial
gene-transfer with viral vectors, it has considerable versatility compared
to transgenic models, where over-expression is constant throughout the
lifespan. Vaccines, while traditionally viewed as prophylactic approaches to
disease, are increasingly being viewed as therapeutic adjuncts in cancer and
cardiovascular disease. Others of us (DM and KU) have found that
immunization of transgenic mouse models of amyloid over-expression with the
All peptide, is surprisingly effective in reducing the Alzheimer phenotype,
both pathologically and behaviorally, that develops in this model of the
disease. This application will use the new rat model of alpha-synuclein over
expression to test the hypothesis that vaccination against alpha-synuclein
could diminish the toxicity of this agent towards dopamine producing
neurons. We will use immunization with whole recombinant protein and
synthetic peptides and immunization with DNA vaccines. Initial studies will
verify that these vaccination regimens can indeed produce high antibody
titers in rats, and determine the active immunization regimen(s) that leads
to high stable titers. We will next test the hypothesis that antibodies
against synuclein produced by these vaccines can arrest the neurotoxicity of
dopaminergic neurons caused by alpha-synuclein over expression.
Additionally, we will examine direct injections of anti-synuclein antibodies
into the brain, bypassing the blood-brain barrier, to evaluate the
effectiveness of this approach in rescuing dopaminergic neurons. Success
will encourage further development of a vaccine as a therapeutic agent in
PD.
Thesaurus Terms:
Parkinson's disease, alpha synuclein, nonhuman therapy evaluation, synthetic
vaccine, vaccine development, vector vaccine
Lewy body, antiantibody, disease /disorder model, dopamine, neuron, passive
immunization, recombinant protein, synthetic peptide biotechnology, cell
sorting, computer program /software, enzyme linked immunosorbent assay,
green fluorescent protein, immunocytochemistry, laboratory rat
Institution: UNIVERSITY OF SOUTH FLORIDA
4202 E FOWLER AVE
TAMPA, FL 33620
Fiscal Year: 2002
Department: PHARMACOLOGY AND THERAPEUTICS
Project Start: 01-FEB-2002
Project End: 31-JAN-2004
ICD: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
IRG: ZNS1
----
Grant Number: 1R01NS041799-01
PI Name: MEREDITH, GLORIA E.
PI Email: meredithg@umkc.edu
PI Title:
Project Title: Synaptic Proteins, Trophic Factors and Neurodegeneration
Abstract: Description (Provided by applicant): One of the most fundamental
questions related to the progressive nature of neurodegeneration in human
disease is how neurons die. Protecting nerve cells against morphological
decline and death requires blocking intrinsic factors that inhibit neural
repair. In the present proposal, we offer an innovative approach to study
those factors that are active in Parkinson's disease (PD) in a new mouse
model that shows synaptic loss and irreversible nigrostriatal degeneration.
We propose to track changes of a key synaptic protein, a-synuclein, both in
its native environment at presynaptic terminals and under neurotoxic
conditions, when it becomes insoluble and accumulates. We will further
correlate those changes with altered neurotrophic support. We have
established an animal protocol by treating C57/bl mice with a combined
regimen of 10 doses of probenecid at 250mg/kg and MPTP at 25mg/kg for 5
weeks. These mice show a slow, progressive loss of nigrostriatal
dopaminergic function for at least 6 months, that mimics PD, with no signs
of recovery. Three weeks after drug treatment, there is a significant
reduction in the number of substantia nigra (SN) cells and dramatic changes
in the subsynaptic distribution and density of a-synuclein-immunoreactive
terminals. These changes could signal the beginning of a chain of events
that leads to cell death. In this proposal, we will focus on the progressive
deterioration of dopaminergic neurons in the SN and their inputs, and
present three specific aims to be addressed through a series of hypotheses.
Specifically, we plan to 1) ascertain the origin and neurochemical phenotype
of synapses in the SN that contain a-synuclein and to establish whether MPTP
+ probenecid treatment leads to their degeneration; 2) determine, in the
MPTP+P model, the temporal relationships between cell death and
a-synuclein-positive synapses, decline in dopamine function and behavior;
and 3) ascertain whether changes in a-synuclein expression and production
are precipitated by altered neurotrophic support. The overall objective of
our research is to understand the relationship between the synaptic protein,
a-synuclein, neurotrophic support, especially brain-derived neurotrophic
factor (BDNF) and their respective roles in the PD form of
neurodegeneration. The findings of this research should shed light on target
areas where neuroprotection strategies can be implemented.
Thesaurus Terms:
Parkinson's disease, alpha synuclein, brain derived neurotrophic factor,
neural degeneration, protein structure function, substantia nigra, synapse
Lewy body, cell death, neurochemistry, neuron electron microscopy,
fluorescence microscopy, image processing, immunocytochemistry, in situ
hybridization, laboratory mouse, methylphenyltetrahydropyridine, polymerase
chain reaction, statistics /biometry
Institution: UNIVERSITY OF MISSOURI KANSAS CITY
5100 ROCKHILL RD
KANSAS CITY, MO 64110
Fiscal Year: 2002
Department: BASIC MEDICAL SCIENCES
Project Start: 01-MAY-2001
Project End: 30-APR-2005
ICD: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
IRG: ZNS1
----
Grant Number: 7R01AG017984-02
PI Name: SIERKS, MICHAEL R.
PI Email: sierks@asu.edu
PI Title:
Project Title: INHIBITING AGGREGATION WITH PHAGE DISPLAY ANTIBODIES
Abstract: Altered protein processing including misfolding and aggregation is
a frequent occurrence in aging neurons compared to younger cells. A number
of neurological diseases such as Alzheimer's Disease (AD) and Parkinson's
Disease (PD) have been connected with increased misfolding and aggregation
of specific proteins or peptides. Beta-amyloid (Abeta) is involved in the
progression of AD through formation of extracellular amorphous plaques and
neurotoxic fibrils, while alpha-synuclein is involved in the progression of
PD through formation of intracellular fibrillar aggregates. Different
variants and morphologies of Abeta and alpha-synuclein have been correlated
with increased formation of the neurotoxic aggregates. Early detection and
subsequent inhibition of neurotoxic aggregate formation can slow or stop the
progression of such diseases. The long term goal of this project is to
develop antibody fragments which can be used to identify critical protein
morphologies which promote neurotoxic aggregate formation; and to engineer
these antibodies so they can inhibit formation of these aggregates in vivo
as a potential treatment. Phage display antibody libraries will be utilized
to isolate pools of single chain antibody fragments (scFvs) which bind to
particular morphologies of Abeta and alpha synuclein. The specific aims of
this proposal are to use phage display antibody libraries to; 1) isolate
scFv antibody fragments specific to various lengths, conformations and
morphologies of Abeta, 2) isolate scFvs specific to various morphologies of
wild-type and mutant alpha-synuclein proteins, 3) identify which of these
scFv antibodies can inhibit either Abeta or alpha-synuclein aggregation and
fibril formation in vitro, which of these scFv antibodies can inhibit either
Abeta or alpha-synuclein aggregation and fibril formation in vitro, and 4)
increase the specificity of these antibodies as needed for imaging and
inhibiting aggregation of Abeta or alpha- synuclein under in vivo
conditions. Antibody specificity will be increased by subjecting the
isolated parent antibody to random mutagenesis of targeted antibody blinding
regions. From this pool of second generation antibodies, scFv fragments with
increased specificity will be isolated. These high-specificity antibodies
will be tested for their ability to inhibit formation of neurotoxic
aggregates under in vivo conditions. Protein aggregation will be monitored
using different techniques including Thioflavin T staining, atomic
microscopy, and electron microscopy.
Thesaurus Terms:
alpha synuclein, amyloid protein, antibody, inhibitor /antagonist, peptide
library, protein engineering, protein structure
Alzheimer's disease, Parkinson's disease, antibody specificity, chemical
aggregate, gene mutation, molecular pathology, protein binding atomic force
microscopy, electron microscopy
Institution: ARIZONA STATE UNIVERSITY
TEMPE, AZ 85287
Fiscal Year: 2002
Department: CHEMICAL & MATERIALS ENGINEERG
Project Start: 01-MAY-2000
Project End: 30-APR-2004
ICD: NATIONAL INSTITUTE ON AGING
IRG: ZAG1