HUNTINGTONS DISEASE

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HUNTINGTONS DISEASE

• Histopathology and the Cytopathological Features

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DEFINITIONS

• Histopathology The tissue changes that affect
  part or accompany a disease

Cytopathology A branch of pathology that deals
with manifestations of disease at a cellular
level
Taken from dictionary.com
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THE HUNTINGTIN PROTEIN

• Huntingtin is a 350kilodaton protein that
  regulates the transcription of Brain Derived
  Neurotrophic Factors (BDNFs).
• BDNFs are pro-survival factors produced by the
  cortical neurons of the brain. They are
  necessary for the survival of the striatal
  neurons in the brain.A mutated version of the
  Htt protein can lead to decreased levels of
  BDNFs being synthesised therefore the neurons
  will not receive as much support. This can result
  in neuron death.

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PROTEIN AGGREGATES

• Mutated Htt proteins can contain 40 glutamines
  (in comparison with the normal 10-35).
• Glutamine is polar and so can make bonds within
  and outside the protein.
• This turns what would be a functionally folded
  protein into a ridged, tangled clump known as a
  protein aggregate.

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NEURONAL INCLUSIONS

• Having excess Glutamine can also lead to another
  form of protein bundling called neuronal
  inclusions.
• NIs form at the axons and dendrites of nerve
  cells in specific areas of the brain and damage
  the neurons.
• NIs can cause structural changes to the cell and
  can interfere with normal protein production
  which again can lead to neuron damage or death.
• Another problem is that an enzyme splices Htt
  into smaller fragments which enter the cell
  nuclei and clump at the centrosome.

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Htt THE KIDNAPPING PROTEIN

• A recent John Hopkins University study has
  revealed that mutated Htt entangles and inhibits
  CREB (a binding protein that is key for cell
  survival).
• They found that the glutamine regions on CREB
  interacted with the extra glutamines on the Htt
  protein.
• This interaction pulls the CREB away from the
  nucleus and prevents it from functioning.
• However researchers have come up with an answer,
  they inserted engineered CREB which lacked the
  glutamine repeats and so couldnt interact with
  the Htt.
• This worked and the nerve cells lived.

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QUALITY CONTROL IN THE CELL

• Healthy cells have a quality control mechanism
  called the ubiquitin-proteasome system (UPS).
• In a healthy cell this system tags mis-folded
  proteins so they can be broken down and the amino
  acids recycled
• However in HD this system fails and aggregates
  accumulate.

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NEUROBIOLOGY

• The group of cells that are most affected in HD
  are found at the base of the brain and are
  collectively known as the Basal Ganglia.
• The BG is responsible for muscle driven (motor)
  movements of the body.
• The Basal Ganglia is split into 2 major regions
  called the Caudate and the Putamen.
• Together these regions are known as the
  Striatum.

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The striatum is highlighted in blue. The lower
section of blue is the putamen and the higher
section is the caudate nucleus
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HD sufferers have enlarged spaces in their Basal
Ganglia due to the death of the nerve cells in
the striatum.Other areas of the brain are
affected too but it appears that the BG is hit
the hardest by the disease.
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SUMMARY

• The Huntingtin Protein (Excess Glutamine)
  Protein AggregatesNeuronal InclusionsKidnap
  ping
• UPS System Fails
• Basal Ganglia Degenerates

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References

• Colour coded Brain Picture from www.anc.ed.ac.uk
• Definitions taken from www.dictionary.com
• Information and rest of the pictures taken from
  www.hope.com