Lecturer: Dr Lucy Patston

 Thank you to the following 2013 Year Two students who devoted their time and effort to developing the following seminar topic:  Kaspara Chaise  Matthew Selby  Bryan Ellis  Some content may differ from that originally created by these students

 Named after George Huntington ◦ Published a paper in 1872 comprehensively describing the disease  Autosomal Dominant Disease  Primarily affects neurologic function  Caused by gene mutation

 Huntington’s disease (HD) is an inherited disorder and is not contagious  HD is a dominant disease; A person needs only to inherit one copy of the mutated Huntington gene to develop HD  Consequently every child of a person with HD has a 50% chance of inheriting the gene and developing the disease. (fig. 1.)

 Psychiatric & Behavioral disturbance  Mood swings, irritability and depression (these eventually decline into Dementia)  Involuntary movement of arms and legs  Formally called Huntington Chorea from the Greek Khoreia, “dance” because of the uncontrolled (twitching, jerking, writhing) movement of the limbs and dystonia (muscle contractions that lead to twisting movements and abnormal postures)

 1 in born with mutated gene in western European decent populations  Approximately 1 in 1 million in Asian and African populations  Video clip of HD sufferer ◦

 Symptoms do not commonly appear until approximately 40 years of age  Symptoms can appear as early as one year of age and manifest different features such as: lack of movement, a rigid body and seizures  Age of onset can decrease with each successive generation

 Born carrying mutation  Initially live with no ill effects  Effects accumulate in brain over time

As the disease progresses, walking and speech become more difficult, and memory and intellectual functions continue to decline  High risk of suicide and suicidal thoughts HD causes death usually 20 years after onset

 Affected gene causing HD is called IT15 ◦ Found on short arm of chromosome 4 (autosomal rather than being on a sex chrosome)  HD mutations are dominant ◦ Those who inherit the mutation will develop the disease if they live long enough  HD gene is expressed as the protien Huntingtin in all mammalian cells

 All IT15 alleles have a section of trinucleotide repeats of cytosine-adenine-guanine (CAG)  Repeats always number <36 in a normal allele, triplet repeats of <39 are reliably associated with development of the disease (fig.2.) GENOTYPE

 Coding of CAG forms the amino acid glutamine  During protein synthesis IT15 is transcribed into mRNA and translated into amino acids forming a polypeptide chain  CAG creates a polyglutamate section within the polypeptide  Normal Huntingtin proteins interact with other proteins in the brain to support healthy brain cells and brain function

 Protein transcribed from mutated allele has extra long polyglutamate chains  The chains fold and alter the tertiary structure of the protein resulting in alterd function (fig. 3.)

 Essential for: ◦ Proper cell division ◦ Programmed cell death (a normal part of cell lifecycle)  Interacts with many other proteins in the brain ◦ Including those involved in:  Transcription  Cell signalling  Intra-cellular transportation

 Mutated huntingtin protein causes neurons in the brain to malfunction and die  First target is always the striatum (part of the basal ganglia) ◦ Severe atrophy of the striatum and its projections is observed in HD patients post mortem (fig. 4.)  With progression, no brain structure is spared  As an area is damaged, symptoms associated with the function of that area appear

 Responsible for planning, habit-learning and modulating movement (often inhibiting it) ◦ The loss of its neurons leaves uninhibited, inappropriate movement  Has links to mood neurons ◦ With mood disturbance being a characteristic of the disease

4

 Caused by extra long polyglutamate chains of mutant protein that break off easily  Glutamine is a charged molecule ◦ Excess causes proteins to link and ‘clump’ instead of taking normal folded form ◦ Resulting tangled masses are called protein aggregates  Both huntingtin and the proteins it interacts with become caught up in the aggregates resulting in: ◦ Loss of proper protein function ◦ Proteins become toxic to brain cells causing loss of brain tissue (fig. 4.)

 The extent of brain cell death increases with the number of CAG repeats, which explains the earlier onset of the disease (phenotype variation) with longer CAG repeats (genotype variation) (Fig. 5.)

Fig. 5.

 Genetic testing is available in New Zealand but strict conditions apply  Only people over 18 years of age are eligible ◦ counselling is required before and after testing ◦ less than 5% of those concerned actually carry out the test (mostly because there is no cure)

 Fetuses can be tested, allowing parents the option of termination if the baby is found to carriy the HD mutation  In vetro fertilization (IVF) embryos can also be tested, allowing implants free from mutation ◦ Funded in a limited way ◦ At risk parent generally tested first

 Would it be for the baby's own good?  Can people chose their children's genetic characteristics? ◦ May set presedents leading to selective implantation based on non-medical features? ('I want a baby with blue eyes!')  Would you want to know at what age you are most likely to die?  If you knew, would getting life insurance be a problem?

 Currently there is no cure for HD  Neurogenesis ◦ New replacement brain cells in a diseased adult human brain  Stem cells ◦ Neural stem cells

 Stem cells ◦ Embryonic stem cells ◦ Embryonic germ cells ◦ Adult stem cells

 In theory ◦ Stem cells from the same person ◦ Avoids rejection

 tington's_Disease_2011.pdf tington's_Disease_2011.pdf  tisit.htm tisit.htm  Marieb, E. N., & Hoehn, K. (2007). Human anatomy & physiology (7th ed.). San Francisco, CA: Pearson Benjamin Cummings.