Nucleic Acids (part 1)

what kind of disease is Huntington’s Disease?

•  An autosomal dominant disease

• autosomal- only effects non sex chromosomes

• Dominant- only need one copy of allele

What is Huntington’s Disease a result of?

 A result of the huntingtin (HTT) gene, repeating a codon multiple (many dozens) of times

◦This codon is CAG, which codes for the amino acid glutamine

What does the mutation of huntington’s disease result in?

 Results in a mutated protein (mHTT), with a long polyglutamine component

◦Repeated at a minimum of 36 times, up to 120 times.

◦If repeated above 39 times, almost guaranteed pathology (i.e you get the disease)

◦Typically, this only repeats a dozen times in unaffected individuals

What causes hungtintons disease?

• Huntingtons disease Gene containing 35 or more CAG repeats (normal gene contains 10-26)

• Human huntingtin Protien with expanded polyglutamine

• causes degeneration of the basil ganglia

Huntingtons Etiology (cause)

•  Approximately 1:10000 individuals have the mutation

Slightly higher in European populations

•  Almost entirely an inherited mutation, with very few cases of spontaneous Huntington’s

0.1% of cases are spontaneous

What happens if Huntingtons disease is diagnosed from symptoms?

 If diagnosed from the symptoms, rather than from a genetic screen, the average age of diagnosis is approximately 40 years old.

◦Post-diagnosis, people usually live an additional 15-20 years, though quality of life declines from the time of diagnosis

Huntingtons disease pathology ( How does it cause its damage?)

Although the exact reason is uncertain, it is thought that this aggregation of Huntington proteins

 Remember ubiquitin?(Helps us target misfolded protiens) Partially through the (non) degradation of protein aggregates

◦Proteins accumulate through the aggregation of hydrogen bonds between the peptides, becoming an indigestible mass inside of the nucleus of certain cells of the basal ganglia

 Brain develops these protein aggregates, beginning from the basal ganglia and eventually affecting many, if not most, of the cerebrum and portions of the cerebellum

 These protein aggregates are thought to inhibit proper functioning of the cells (neurons in this case), leading to death

Clinical signs/progression of Huntingtons disease

• major symptom:  dysregulated motor function, causing movement disturbances: In later stages, patients find it difficult to move, swallow, etc. Suffer from dystonia (inability to move/control muscles)

• Cognitive dysfunction:patients exhibit memory dysfunction and executive dysfunction

• psychiatric disturbances: Preclinically (i.e. before major disease onset and subsequent diagnosis), patients may exhibit: Depression, mania, delusions, and other psychiatric disorders at considerably higher levels than the average population

• Irritability and aggression are typical of later stage patients

• Sleep and other mood disorders are also common

Symptoms of Hungtingtons disease:

 visual motor symptoms:

◦Chorea – Unpredictable and involuntary muscle movements

◦Dystonia – Also unpredictable movements, but are repetitive and / or twisting motions

◦Combined together, these movements almost look rhythmic, like a combination of fidgeting and dancing

◦Motor impersistence – Can not maintain a voluntary action

◦Patient is asked to hold out their tongue, can not maintain it

◦Lack of fine motor movement

◦Notice the patient will attempt to pinch with their index finger and thumb, but can’t do the fine control

◦Gait disturbances

◦Typically slower, more variable lengths of stride, uncoordinated

What does the regular functioning huntingtin gene do?

• Unknown/unclear, very few other genes with similar sequence homology, so difficult to determine

•  possibly a role in proper neuronal functioning, bc it resides primarily in this area: conditional knockouts (i.e. timed knockouts) of the protein can highly disrupt brain function

•  Animals (mice) that have this gene deleted do not survive

  ◦Demonstrates that the gene is crucial for neuro-development