Shy-Drager/MSA Support Group



   Multiple System Atrophy News


Click figure to go to SDS/MSA Website

March 2002

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

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.

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

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
SDS/MSA Support Group


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
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

- access to the Shydrager mail list
- an annual patient/caregiver/family member meeting with prominent physicians.

Please visit the website at

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

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
EMSA-SG Secretariat:


4. Boston Globe article on MSA
(Contributed by Carol Langer

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)
2. SCA - Spinocerebellar Ataxia (hereditary)



6. News from the Center for Neurodegenerative Disease Research. (Contributed by Steve Crawford

"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.

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."


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



7. National Institutes of Heath - Funded Studies involving Alpha-Synuclein


These studies are all investigating possible treatments which might prevent alpha-synuclein aggregation and thus have potential for Multiple System Atrophy as well. See:


Grant Number: 5P01AG009215-12
PI Email:

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

Fiscal Year: 2002
Project Start: 01-AUG-1990
Project End: 30-APR-2005


Grant Number: 1R43AG020031-01
PI Email:
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

Fiscal Year: 2002
Project Start: 01-AUG-2001
Project End: 30-APR-2002


Grant Number: 1R01AG018440-01A1
PI Email:
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

Fiscal Year: 2002
Project Start: 01-SEP-2001
Project End: 31-AUG-2006


Grant Number: 1R21NS043661-01
PI Email:
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

TAMPA, FL 33620
Fiscal Year: 2002
Project Start: 01-FEB-2002
Project End: 31-JAN-2004


Grant Number: 1R01NS041799-01
PI Email:
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

Fiscal Year: 2002
Project Start: 01-MAY-2001
Project End: 30-APR-2005


Grant Number: 7R01AG017984-02
PI Email:
PI Title:

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

TEMPE, AZ 85287
Fiscal Year: 2002
Project Start: 01-MAY-2000
Project End: 30-APR-2004