Hereditary Disease Foundation
"Huntington’s
Disease: From Molecule to Miracle: Searching for the Cure"
Albert
Parvin Foundation Workshop at the Home of Jennifer Jones Simon
January
11-12, 2003
Los Angeles, CA
Report repared
by Marina Chicurel, Ph.D.
Abstract
One of the most striking features of Huntington’s disease is its
multiple faces, its varied effects on behavior, anatomy, biochemistry, and
electrophysiology. Although the disease has its roots in a single, well-defined
dominant mutation –a CAG expansion in the huntingtin gene-- its consequences
have proved complex and multi-faceted.
Participants at the Albert Parvin workshop suggested that HD is a
multi-hit disease, in which an accumulation of cellular and molecular
dysfunctions ultimately leads to the lack of motor control, cognitive
impairment, and death. They emphasized that elucidating the timing of these
dysfunctions, particularly identifying the earliest alterations, will be
critical, not only for understanding the disease, but for developing therapies.
They also highlighted the importance of resolving the question of whether the
primary source of pathology lies in the direct effects of mutant huntingtin on
striatal cells or on huntingtin’s effects on other cells which interact with
them. In this context, participants discussed huntingtin’s disruptive effects
on cellular transport, neurotransmitter receptor signaling, and the
functionality of cortico-striatal connections.
Several methods for screening candidate drugs were also discussed. The
use of biolistics applied to rodent brain slices, organotypic mouse slice
cultures, and Drosophila aggregation assays, for example, were described.
An increased emphasis on assays that closely reflect the disease process in
humans was proposed, as well as the establishment of criteria to select
therapeutic candidates for clinical trials. In addition, participants reviewed
the status of therapeutic candidates, including regulators of chaperone protein
function, minocycline, and co-enzyme Q10. Of particular interest was the
discussion of histone deacetylase inhibitors, which have recently provided
encouraging results in a mouse model of disease.
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