Huntington`s Disease - Lake Forest College

Huntington’s Disease
Dillon Gilbow, Lauren Leeber, Ashley Reich
Biology Department, Lake Forest College, Illinois, 60045
What is Huntington’s?
• Neurodegenerative disease
• Characterized by aggregates of misfolded proteins
• If gene is inherited the disease is acquired
• Can be detected through blood test
• NO KNOWN CURE
A Molecular Look into the Hunt
Hunting for Relief
Pathway in Huntington’s Disease
Treatment for Chorea Symptoms
Tetrabenazine
Neuroleptics
Benzodiazepines
Inhibits VMAT-2
Blocks Dopamine Receptors
Potentiates GABA Receptors
Post Synaptic Membrane
George Huntington
Post Synaptic Membrane
http://upload.wikimedia.org/wikipedia/commons/9/9f/Georgehuntington.jpg
Onset v. Repeats
Symptoms
Age
Treatment for Psychiatric Symptoms
Presynaptic Membrane
Reuptake
Selective Serotonin Reuptake Inhibitors
Serotonin
CAG Repeats
Correlation between the number of
CAG repeats and age of onset
Death
Serotonin
Huntinton’s Neuron v. Normal Neuron
Post Synaptic Membrane
Phases of signs and symptoms as
disease progresses
Huntingtin Protein
Post Synaptic Membrane
The Hunt for Knowledge
What research is being done for Huntington’s Disease?
CAG nucleotide sequence
AKA: Polyglutamine tract
Location: Chromosome 4
Codes for: Glutamine
• Why are cells dying specifically in the striatum?
• Are neural transplants a viable form of treatment?
CAGCAGCAGCAGCAGCAGCAGCAGCAG
mHtt
Function: Not clearly known
Normal Htt: <36 repeats CAG
Mutant Htt: >36 repeats CAG
repeats of CAG, the
more severe pathology
mHtt forms aggregates
• What molecular pathways are there to degrade protein aggregates?
• Can gene mutations help with possible therapies for HD?
Mutant Huntingtin
* More
Coronal brain section. Severe striatal atrophy in Huntington’s patient
(left) and control (right)
References
• Cattaneo, E., Rigamonti, D., Zuccato, C. (2002) Enigma of Huntington’s Disease. Scientific American.
mHtt
mHtt
mHtt
mHtt
92-97.
• Andrich, J., Epplen, J.T., (2006) Hunting for Answers. Scientific American. 70-75.
• Hayden, M.R., Kremer, B. Huntington’s Disease in The Metabolic and Molecular Bases of Inherited
Disease, (eds Scriver, C.R., Beaudet, A.L., Sly, W.S. & Valle, D.)843−896 (McGraw-Hill, Inc., New York,
1995).
• "Huntington's Disease Information Page." National Institute of Neurological Disorders and Stroke
(NINDS). Web. 02 Apr. 2010. <http://www.ninds.nih.gov/disorders/huntington/huntington.htm>.
Acknowledgments
Lauren, Allie and Dillon would like to thank their peer mentors Keith Solvang, Liza Pahomov, and
Abbey Pipkorn for taking so much time out of their busy schedule to offer their guidance and
wisdom. We would also like to thank Alina Konnikova, as well as the other Bio346 students.
A special thanks to Dr. DebBurman for his never-ending willingness to help us this semester.
Medical Mysteries of HD
Dillon Gilbow, Lauren Leeber, Ashley Reich
Biology Department, Lake Forest College, Illinois, 60045
Hunting for Mutants
Hunting for Striatal Cells
GAP
GAP
Why is there cell
death in the striatum?
Why does Htt only
kill striatal cells?
1
FINDINGS
1
Rhes binds to mutant
huntingtin
2
Rhes decreases
aggregation of mHtt
3
Rhes acts as an E3
protein in
sumoylation
4
Cysteine is required
for mHtt
Htt Rhes
2
mHtt
mHtt
Rhes A phosphomimetic (SD) mutation or a
phosphoresistant (SA) mutation will
help relieve motor and behavioral
deficits, aggregation, and
neurodegeneration.
Rhes UBC
Rhes mHtt
E1
Rhes C263 to Serine
Rhes CELL SURVIVAL
http://upload.wikimedia.org/wikipedia/commons/thumb/3/33/BrainCaudatePutamen.svg/172pxBrainCaudatePutamen.svg.png
Reference: Srinivasa Subramaniam, et al. (2009). Rhes, a Striatal Specific Protein,
Mediates Mutant-Huntingtin Cytotoxicity. Science. 324:1327-1330.
2
1
Mice with the SD mutation
live and are healthy, mice
with the SA mutation die.
2
Mice with any of the SA
mutation usually died in
vitro, all died from HD
eventually, those mice with
the SD mutation were
healthy.
Inflammatory response
How can mutant
huntingtin protein be
degraded?
1
2
Grafts do not survive
long term
Death of projection
neurons
4
Inflammatory
response targets grafts
To target a pathway to
degrade mutant
huntingtin and
increase cell survival.
Htt
T
cells
Patient with Huntington’s
Natural
Killer
10 YEARS LATER
2
FINDINGS
Faster Death
Projection Neuron
Death
More severe case
3
Grafted neurons die
faster than patient’s
neurons
3
GOAL
Natural
Killer
FINDINGS
-/SD
-/SD
-/SD
-/SA
DEAD
DEAD
+/SD
HEALTHY
1
Lysine K444
Lysine K444
Lysine K444
Ac
Ac
Lysine K444
Ac
Lysine K444
HDAC
1
Lysine K444
Lysine K444
AcHAT
Ac
Ac
HDA
HDAC
2
Lysine K444
HAT
Lysine K444
Ac
HAT and deacetylated by
HDAC.
2 Inhibition of HDAC and
increase in HAT leads to
. an
the degradation of mHtt
3
Mutations on lysine may
prevent acetylation and
leads to an increase in cell
death.
http://blogs.abc.net.au/photos/uncategorized/2008/06/27/body.gif
http://scienceblogs.com/purepedantry/upload/2007/04/hippocampus-2.gif
HAT
Lysine K444
The lysine of mutant
1 jjjhuntingtin
is acetylated by
and
increased cell
survival.
3
Patient still has Huntington’s
Reference: Cicchetti, F., et al. (2009). Neural Transplants in Patients with Huntington’s
Disease Undergo Disease-like Neuronal Degeneration. PNAS. 106: 12483-12488.
-/SD
Reference: Gu, X., et al. (2009) Serines 13 and 16 are Critical Determinants of Full Length Mutant Huntingtin Induced Pathogenesis in HD Mice. Neuron. 64:828-840.
Rhes
To replace dying
cells as a viable
treatment
-/SA
Hunting for a Target
T
helper
Cell
GOAL
-/SD
SA/SD
GAP
4
Can dying neurons
be replaced as a
treatment?
+/SD
SA/SA
Hunting for a Treatment
GAP
SA/SA
FINDINGS
E2
E3
4
CELL DEATH
DEAD
SA
Rhes STRONG
WEAK
Area of striatal cell death
3
mHtt Rhes
SD
GOAL
GOAL
Identify the striatal
specific protein, Rhes,
role in HD
HEALTHY
1
Can adding mutations on serines 13
and 16 in transgenic mice lead to a
possible therapy for Huntington’s
Disease?
Lysine K444
Arginine R444
Arginine R444
Ac
3
Arginine R444
References: Jeong, H., et al. (2009). Acetylation Targets Mutant Huntingtin to Autophagosome Degradation. Cell. 137: 60-72.
HDAC