Huntington’s disease is a devastating genetic disorder that typically affects individuals in their
30s and older. Huntington’s symptoms include spastic movements, loss of physical control, a
change in mental state in the eventual inability to communicate or control movement.
These symptoms occur primarily due to the death of neurons in the basal ganglia of the brain.
Basal ganglia are thought to control motor function and be involved in sensory processing. The
death of the neurons are initially triggered by an abnormal Huntington protein in individuals
with the disease.
The Huntington protein is produced by gene found on everyone’s fourth chromosome. The
non-mutated gene ends with a sequence of DNA bases: cytosine, adenine, and quinine or CAG
which codes for a particular amino acid on the protein. However, in the mutated gene the CAG
sequence repeats itself multiple times resulting in a mutant protein with an elongated tail on
that particular amino. Unlike its wild-type or normal protein counterpart: the mutant
Huntingtin protein interacts with the neuron in many dangerous ways.
The mutated Huntington protein is responsible for destroying neurons through a number of
different mechanisms of which we will highlight three.
The addition of channels, the formation of aggregates, and damage to mitochondria.
Addition of channels
Mutant Huntingtin interacts with certain channels called NMDA channels in the neural
membranes. Firstly, mutant huntingtin pulls more NMDA channels than normal into the neural
membrane. The higher number of channels causes a higher influx of both sodium and calcium
ions into the cell. The increased number of ions over stimulates the neuron and damages it.
Mutant huntingtin also binds to a number of proteins also present in the neural membrane next
to the NMDA receptors and activates them, after activation these proteins can run around the
cell and activate other factors that causes cell death or apoptosis.
Formation of aggregates
The higher amount of calcium allowed into the neurons by the high number of NMDA
receptors, also leads to the activation of enzymes called caspases. Caspases are in charge of
chopping up proteins in the neuron, and Huntington’s the higher levels of calcium activate
more caspases which run around the cell and cut apart the extra long mutant huntingtin
proteins.
The mutant huntingtin pieces then clump into clusters of protein fragments called aggregates.
These clumps then trap other important factors in the cell. These aggregates can travel into the
nucleus of the cell and trap proteins that regulate gene expression. For example, when a
particular protein that works with the gene for BDNF is trapped by the aggregates it is not able
to properly regulate the production of BDNF unnecessary, as a result the cells have lower levels
of BDNF than a healthy cell which can then lead to cell death.
Damage to Mitochondria
Another way mutant huntingtin harms the cells is by interfering with the proper function of
their mitochondria. Mitochondria make energy in the form of ATP for neuron and when they
are not working properly, the neurons cannot produce the energy needed to survive. Normally
mitochondria sweat apart through fission and then join together again through fusion. This
process is regulated by many proteins including the DRP one protein, which regulates
mitochondrial fission. Mutant huntingtin binds to dr p1 and leaves the mitochondria unable to
regulate fission so they divide more than they would normally. This mutant huntingtin and DRP
one interaction also makes it more difficult for the mitochondria to fuse back together. The
imbalance between fission and fusion causes the mitochondria to break apart and lose proper
function. Which means less ATP and therefore less energy for the cell.
Conclusion
In addition to these highlighted issues, the mutant huntingtin protein can cause many other
problems associated with the disease. Scientists will continue to investigate the many ways that
mutant huntingtin contributes to the pathology of the disorder, while there is no cure for
Huntington’s a number of therapies are being investigated that many help patients with certain
symptoms of the disease, including the motor difficulties and mood changes. Occupational and
psychological therapies have proved effective in improving day-to-day life for Huntington’s
patients.