The Marker - 2004 - Huntington's Disease Society of America

leader in developing new ways to look
at an often under-diagnosed and
misunderstood neurodegenerative
disease.
As you will read in this issue of
The Marker, HDSA funded research
stands on the cusp of a new and
exciting era that will explore five
significant questions that have
developed through the six years that
the HDSA Coalition for the Cure has
been in existence. The answers to these
questions will not only lead to effective
therapies but will also put the pieces of
the HD puzzle together. The corners of
the puzzle have been fitted together, we
know so much more now about HD; it’s
time for us to work together to fill in
the missing pieces at the center of the
puzzle that will point us to effective
therapies and ultimately a cure.
In future issues of this magazine, you’ll
read more about the newly defined
Coalition for the Cure and HDSA’s
new Drug Discovery Team. But take a
moment to look at what HDSA’s $20
million investment in research,
through the prestigious Coalition for
the Cure and innovative Grants and
Fellows program, has accomplished
in just six short years through the
generous support of donors like you.
This impressive list is broken down
into four major areas of
accomplishment: discoveries through
‘basic’ research; breakthroughs using
cell and animal models; advances
through pre-clinical translational
research; and findings from clinical
research and trials. Each link in the
chain notes the HDSA funded
Coalition investigator or grant/fellow
recipient who helped to fit together
the corner pieces of the HD puzzle.
MILESTONES
IN HDSA FUNDED RESEARCH
I. BASIC RESEARCH:
Huntingtin Gene
a. variation of CAG repeat length
accounts for variation of age of onset
(Drs. Marcy MacDonald, James
Gusella, Michael Hayden,
Christopher Ross)
b. instability of CAG repeat length
accounts for anticipation
(Drs. MacDonald, Hayden, Ross,
Gusella)
c. variation in CAG repeat length in
different neurons may contribute to
cell death (Dr. Peggy Shelbourne)
d. other genes may modify age of onset
of HD (Drs. Gusella, Ross, Hayden)
Huntingtin protein
a. Normal function of huntingtin
b. HD is predominantly caused by
toxic activity of mutant huntingtin
(Dr. Elena Cattaneo)
c. loss of normal huntingtin may
contribute to HD (Drs. Hayden,
Cattaneo)
d. interaction partners of huntingtin
help clarify its abnormal function
(Drs. Ross, Hayden, MacDonald,
Erich Wanker)
Aggregation
a. Mutant huntingtin promotes
formation of insoluble aggregates
(Dr. Wanker)
b. Insoluble clumps of proteins found in
brains of HD mouse models
(Drs. Wanker, Bates, Davies)
c. Insoluble clumps of proteins also
found in human HD brains
(Drs. Wanker, Marian DiFiglia, Ross)
d. Aggregation prevents cell from
degrading old and damaged proteins
(protesome) (Drs. Ron Kopito, Wanker,
Rick Morimoto)
Proteolysis
a. Huntingtin protein is cut into pieces
by proteases which may generate a
toxic fragment (Drs. Hayden, Ross,
DiFiglia, Lisa Ellerby)
Metabolism
a. Metabolic derangements can mimic
toxicity seen in HD (Drs. M. Flint
Beal, J. Timothy Greenamyre)
b. HD involves metabolic abnormalities
(Drs. Beal, Greenamyre, Akira Sawa)
c. Huntingtin can directly interfere
with mitochondrial metabolic function
(Dr. Greenamyre)
Transcription
a. Mutant huntingtin interferes with
normal gene transcription (Drs. Leslie
Thompson, Ross, Jang-Ho Cha,
Steven Hersch)
b. Nuclear location of huntingtin
enhances toxicity (Dr. Ross)