huntington’s disease - lake forest college
TRANSCRIPT
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
Dillon Gilbow, Lauren Leeber, Ashley Reich Biology Department, Lake Forest College, Illinois, 60045
What research is being done for Huntington’s Disease?
• Why are cells dying specifically in the striatum?
• Are neural transplants a viable form of treatment?
• What molecular pathways are there to degrade protein aggregates?
• Can gene mutations help with possible therapies for HD?
Huntingtin Protein
A Molecular Look into the Hunt Hunting for Relief
mHtt
CAG nucleotide sequence
AKA: Polyglutamine tract Location: Chromosome 4 Codes for: Glutamine
Mutant Huntingtin
Function: Not clearly known Normal Htt: <36 repeats CAG Mutant Htt: >36 repeats CAG
* More repeats of CAG, the more severe pathology
mHtt forms aggregates
CAGCAGCAGCAGCAGCAGCAGCAGCAG
mHtt
mHtt
mHtt
Huntington’s Disease
Treatment for Chorea Symptoms
Treatment for Psychiatric Symptoms
Tetrabenazine
Symptoms Onset v. Repeats
Neuroleptics Benzodiazepines Blocks Dopamine Receptors Potentiates GABA Receptors Inhibits VMAT-2
Post Synaptic Membrane Post Synaptic Membrane
mHtt
Correlation between the number of CAG repeats and age of onset
Coronal brain section. Severe striatal atrophy in Huntington’s patient (left) and control (right)
The Hunt for Knowledge
Pathway in Huntington’s Disease
Huntinton’s Neuron v. Normal Neuron
George Huntington http://upload.wikimedia.org/wikipedia/commons/9/9f/Georgehuntington.jpg
Post Synaptic Membrane Post Synaptic Membrane
Reuptake
Selective Serotonin Reuptake Inhibitors
Presynaptic Membrane
Serotonin
Serotonin
References
Acknowledgments
Phases of signs and symptoms as disease progresses
• Cattaneo, E., Rigamonti, D., Zuccato, C. (2002) Enigma of Huntington’s Disease. Scientific American. 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>.
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.
CAG Repeats Death
Age
Medical Mysteries of HD Dillon Gilbow, Lauren Leeber, Ashley Reich Biology Department, Lake Forest College, Illinois, 60045
Hunting for Mutants
Rhes binds to mutant huntingtin
Rhes decreases aggregation of mHtt
Rhes acts as an E3 protein in sumoylation
Cysteine is required for mHtt
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.
Htt WEAK
Rhes
STRONG
CELL DEATH CELL SURVIVAL
Area of striatal cell death
UBC
E1
Rhes
E2 E3
Rhes
Reference: Srinivasa Subramaniam, et al. (2009). Rhes, a Striatal Specific Protein, Mediates Mutant-Huntingtin Cytotoxicity. Science. 324:1327-1330.
http://upload.wikimedia.org/wikipedia/commons/thumb/3/33/BrainCaudatePutamen.svg/172px-BrainCaudatePutamen.svg.png
Can dying neurons be replaced as a treatment?
To replace dying cells as a viable treatment
Patient with Huntington’s
Patient still has Huntington’s
More severe case
10 YEARS LATER
Faster Death
Natural Killer
Natural Killer
T cells
T helper
Cell
Rhes
Htt
Inflammatory response
Projection Neuron Death
Hunting for a Treatment
Lysine K444 Lysine K444
HAT
Ac
Why does Htt only kill striatal cells?
Rhes
Rhes Rhes
Rhes
Rhes mHtt
mHtt
mHtt
mHtt
1
2
3
4
Hunting for Striatal Cells
GAP
GOAL
FINDINGS
Why is there cell death in the striatum?
Identify the striatal specific protein, Rhes, role in HD
Hunting for a Target
GAP
GOAL
FINDINGS
How can mutant huntingtin protein be degraded?
To target a pathway to degrade mutant huntingtin and increase cell survival.
The lysine of mutant jjjhuntingtin is acetylated by HAT and deacetylated by HDAC.
Inhibition of HDAC and an increase in HAT leads to the degradation of mHtt and increased cell survival.
Mutations on lysine may prevent acetylation and leads to an increase in cell death.
1
2
3
4
GAP
GOAL
FINDINGS
Grafts do not survive long term
Grafted neurons die faster than patient’s neurons
Death of projection neurons
Inflammatory response targets grafts
1
2
3
4
http://blogs.abc.net.au/photos/uncategorized/2008/06/27/body.gif http://scienceblogs.com/purepedantry/upload/2007/04/hippocampus-2.gif
Lysine K444 Lysine K444 HAT
Ac
Lysine K444
Ac
HDAC HDAC
Lysine K444 Ac
Lysine K444
Ac
HDAC HDA
Lysine K444
Ac
Lysine K444 Lysine K444 HAT
Ac
Lysine K444
Arginine R444
Arginine R444
Ac
Arginine R444
2
1
3
4
Reference: Cicchetti, F., et al. (2009). Neural Transplants in Patients with Huntington’s Disease Undergo Disease-like Neuronal Degeneration. PNAS. 106: 12483-12488.
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2
3 3
References: Jeong, H., et al. (2009). Acetylation Targets Mutant Huntingtin to Autophagosome Degradation. Cell. 137: 60-72.
SA
SD
+/SD
-/SA
-/SD
-/SD
SA/SD
SA/SA
1
2
-/SD -/SD
-/SD -/SA
+/SD
HEALTHY
DEAD
HEALTHY DEAD DEAD
GAP
GOAL
FINDINGS
Can adding mutations on serines 13 and 16 in transgenic mice lead to a possible therapy for Huntington’s Disease?
1
2
A phosphomimetic (SD) mutation or a phosphoresistant (SA) mutation will help relieve motor and behavioral deficits, aggregation, and neurodegeneration.
Mice with the SD mutation live and are healthy, mice with the SA mutation die.
Mice with any of the SA mutation usually died in vitro, all died from HD eventually, those mice with the SD mutation were healthy.
C263 to Serine
1
2.
SA/SA
3