Very encouraging. Here is more on this.

Kathleen
===========================
http://www.hhmi.org/news/lindquist_20081120.html


November 20, 2008
Discovering New Strategies to Treat Neurodegenerative Diseases

Susan Lindquist believes that if "personalized medicine" for complex
neurodegenerative disorders is to become a reality then scientists must
begin developing more rigorous approaches to identifying and validating
promising new therapies.

Although personalized medicine offers tremendous promise for developing new
medical treatments that are tailored specifically to a patient's genes,
researchers moving in to this nascent field face formidable challenges: For
example, some scientists feel they still know too little about the molecular
underpinnings of diseases to begin designing personalized treatments. And
although scientists have discovered many candidate genes for diseases, the
research to validate those genes as legitimate drug targets has proceeded
very slowly.

Undaunted by those challenges, Howard Hughes Medical Institute investigator
Susan Lindquist is using a new Collaborative Innovation Award from HHMI to
forge ahead. Her team's goal is to discover new strategies to target the
biological mechanisms that break down in Parkinson's disease and other
neurodegenerative disorders. "The idea behind our project is to transition
to a new era in medicine," says Lindquist, who is also a member of the
Whitehead Institute for Biomedical Research.

Lindquist and her collaborators have developed an action plan that will
exploit the powerful tools available to study gene function in three
different model organisms (yeast, worms and mice) and integrate genetic data
from large-scale studies of people who have Parkinson's disease. Their plan
also calls for using new stem cell technology to generate cellular and
animal models that can be used in screening for new drug therapies to treat
neurodegenerative diseases.

Even if they fail to bring personalized medicine closer to reality,
Lindquist says the risk of inaction is far greater. She prefers to take the
long view: "We may fail," she concedes. "But HHMI is confident that even if
we do, we're going to learn an awful lot and generate information that's
important."

Her bold proposal unites top experts from multiple disciplines - a sort of
"scientific dream team." As independent researchers, Lindquist and her
collaborators have made important discoveries about the basic biology of
diseases ranging from neurodegenerative disorders to cancer to sickle cell
anemia and diabetes.

Lindquist, an expert on protein folding, will join forces with Rudolf
Jaenisch, a stem cell and cloning pioneer who is also at the Whitehead.
Other members of the dream team are: Richard Myers, who studies the genetics
of Parkinson's disease at Boston University School of Public Health; Guy
Caldwell at the University of Alabama, Tuscaloosa, who has developed
roundworm models of dopamine neuron degeneration; and Jean-Christophe Rochet
of Purdue University, whose research probes how the buildup of misfolded
proteins damages nerve cells.

Parkinson's disease is one of the neurodegenerative diseases at the top of
the group's "to study" list. The disease causes progressive deterioration of
dopamine neurons in the brain, leading to muscle rigidity, tremors, balance
problems and mental decline. The scientists will also tackle Huntington's,
amyotrophic lateral sclerosis, and other diseases that are still to be
determined, says Lindquist.

Over the years, various research teams have shown that improper protein
folding plays a major role in severe neurological disorders, including
Huntington's disease and Parkinson's disease. Lindquist and others have
shown that a neurotoxic form of the alpha-synuclein protein causes a lethal
buildup of proteins inside dopamine-producing neurons. Her team developed a
model of alpha-synuclein toxicity in yeast and used that model system to
identify dozens of genes that affect protein folding. Some of these genes
help cells cope with the surfeit of misfolded proteins and may therefore
provide blueprints for the design of new drugs to treat neurodegenerative
disorders.

Building on those studies, Lindquist's group will first do chemical and
genetic screens in yeast to identify additional genes and small molecules
that can be validated as new drug targets and/or potential therapies.
Validation is a tedious but crucial part of drug discovery: Researchers use
a variety of assays to determine whether a molecule plays a key role in the
onset or progression of a disease. In those studies, they also assess
whether interfering with or enhancing the activity of that molecule has an
impact on disease symptoms and progression.

Lindquist notes that the collaborative HHMI project "will take the
validation process to an entirely new level" by testing potential drug
compounds in yeast, nematode worms, cultured rat neurons, and in both mouse
cells and in mice derived from mammalian embryonic stem cells. For expertise
in new cloning and stem cell manipulation techniques, Lindquist will turn to
Jaenisch, a leader in the pursuit of patient- and disease-specific stem
cells designed for research.

Jaenisch will use a relatively new technique to reprogram both mouse and
human adult fibroblast cells back to near-embryonic status. Those
reprogrammed cells, called induced pluripotent stem (iPS) cells, can then be
further tweaked to differentiate into desired populations of cells,
including the dopamine-producing neurons that are attacked in
neurodegenerative diseases.

The scientists believe that if they are successful, their work will provide
much needed new animal models for testing therapies for other
neurodegenerative diseases and complex multifactorial diseases. Lindquist
and her collaborators will use these mice to test the neuroprotective
effects of specific genes that she and others have been putting through
their paces in yeast and cultured rat neurons.

The mice will also give researchers an unprecedented opportunity to learn
how misfolded proteins, aberrant protein trafficking and environmental
factors interact to produce devastating neurodegenerative disorders. "The
long-term goal is to develop personalized therapeutic interventions for very
complex diseases," said Lindquist.

For someone who has spent her career on the frontline of basic research,
Lindquist is invigorated by the chance to work on such a promising
translational project - something she has long avoided as "too hard."

"To me the thought that people could actually be living better lives because
I've done something - that is really exciting," she says.


2008/11/21 Carolyn Stephenson <[log in to unmask]>

> UA researcher chosen for innovative Parkinson's study
>
> By Adam Jones, Staff Writer
> Published: Thursday, November 20, 2008 at 3:30 a.m.
> Last Modified: Wednesday, November 19, 2008 at 11:12 p.m.
>
> http://tinyurl.com/67p2lu
>
> Excerpts:
> "What's most exciting about this grant is that it goes beyond the realm of
> halting the disease and actually is looking at trying to stop it," said Guy
> Caldwell, a UA professor known in biological circles for his work using
> microscopic worms to study genes.
>
> The teams are led by institute "investigators," leading scientist in each
> team's field. The lead investigator on Caldwell's team is Susan Lindquist
> of
> the Massachusetts Institute of Technology, and other members include a
> biological engineer at Purdue University, another MIT researcher and a
> geneticist at Boston University School of Public Health.
>
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