Unraveling the Pathology Behind Huntington’s Disease

By Scott Song (Senior Editor)

Huntington’s disease (HD) is an autosomal dominant (only a single mutated gene is necessary to inherit the disease) neurodegenerative disease characterized by the loss of medium spiny neurons in the striatum. This is due to the repetition of “CAG” (cytosine-adenine-guanine) nucleotides,  which codes for glutamine on the Huntington (Htt) gene. Medium spiny neurons are especially important in regulating the movement of the entire body, including the eyes. The Htt gene codes for the Htt protein, which functions as a scaffold protein and assists in intracellular trafficking and axonal transport.

Because the Htt protein is largely responsible for the transmission of messages between neurons, research on HD have investigated cellular responses to these messages. In particular, research has focused on molecules released in response to messages received at the synapse of a neuron called secondary messengers. Secondary messengers are responsible for controlling cell survival, growth, and apoptosis. In particular, past research has focused on investigating calcium, an essential secondary intracellular (within a cell) messenger for neurons. The influx of calcium into neurons is initiated by depolarization, which opens voltage-gated calcium channels (VGCC) and allows calcium to enter through the cell membrane. This influx acts as a signal, which regulates the release of neurotransmitters presynaptically, controlling the response of postsynaptic dendrites, regulating gene transcription, and promoting neuronal growth. Thus, calcium regulates neuronal activity both locally and globally in a neural network. Within neurons, calcium homeostasis maintained by ER and and mitochondria.

Dyshomeostasis of calcium levels in diseased HD neurons is caused by calcium binding protein interactions with mHtt, resulting in mitochondrial stress from excess calcium uptake. The mutant Htt (mHtt) protein leads to an increase in intracellular calcium levels which results in neuronal cell apoptosis. Abnormal mHtt protein raises intracellular cytosol calcium levels, increases mitochondrial matrix calcium levels, and decreases endoplasmic reticulum (ER) calcium levels. Furthermore, calcium flow is severely impaired in HD neurons through a variety of receptors on both the membrane and within the cell. These include NMDAR (N-methyl D-aspartate receptor), VGCC (voltage-gated calcium channel), SOC channels (store-operated calcium channels), and InsP3R1 (inositol1,4,5-trisphosphate receptor). To summarize, mHtt affects interactions with calcium-binding proteins and mitochondrial membranes, regulates calcium influx from outside the neuron, and release of calcium from intracellular stores.

mHtt protein also causes a decrease in transport of brain derived neurotrophic factors (BDNF), a protein that promotes neuronal survival, from the cortex to the medium spiny neurons. Neurons in the motor cortex form synapses with striatal medium spiny neurons, providing BDNF to the striatum. BDNF binds to receptors present on the medium spiny synapse and initiates a signaling cascade. The loss of this initial signal and cargo along the cortico-striatal axis causes the deterioration of striatal medium spiny neurons.  

The onset of HD is in the 30s or 40s, with progressive neurodegeneration in the parts of the brain that control thinking, emotion, and movement. HD is characterized by involuntary jerking or writhing movements (chorea), along with a decline in mental abilities and development of psychiatric problems. The disease is fatal within 10-20 years. Currently, there is no cure for Huntington’s disease nor is there an effective treatment capable of delaying the progression of the disease. However, research targeted towards detailing specific pathological pathways of the disease’s progression will provide the backbone for translational research in finally curing Huntington’s Disease, and other similar neurodegenerative diseases.

Vivian Lu