HTT is highly expressed in striatum. The striate nucleus or striatum is the subcortical part of the forebrain and it is the major input station of the basal ganglia system. It is the first area to be affected with HD. Striatum volume loss occurs before symptom onset and when HD is diagnosed it has undergone a 50 % volume reduction. HTT is also subcellular located in somatodendritic regions and it is also associated with microtubules.

 

It has been reported in several studies that mutations hamper anchoring of cytoskeletal and the transport of different organelles, mitochondria, vesicles and molecules.

 

HTT is a transglutaminase substrate and forms polymers preferentially if HTT bears polyglutamine expansion (OMIM: 613004). This protein regulates brain-derived neurotrophic factor (BDNF) transcription. BFNF is produced by cortical neurons and it allows the survival of cortical neurons in the brain. The production of this factor decreases when HTT becomes mutated. Striatal neuron death is its direct consequence. Other brain regions can be affected by HD such as thalamus, globus pallidus, subthalamic nucleus, white matter, substantia nigra, cerebral cortex, cerebellum and hippocampus. The affected area correlates to symptom variation.

 

Sixteen HEAT (Htt elongation factor 3) repeats have been identified in HTT structure and they are organised in four clusters although their biological function has not been determined.

 

 

PATHOGENESIS

 

Symptomatology of Huntington disease is due to a selective degeneration of neurons in the caudate and putament. Degeneration of medium spiny provides neurobiological basis for chorea because of alterations in enkephalin-containing neurons of the indirect pathway of movement control.

Cortex, hippocampus and substantia nigra can be also altered.

 

Huntingtin proteolysis produces N-terminal fragments bearing polyglutamine tracts and these fragments display neuronal toxicity and aggregation in neuronal intranuclear inclusions and dystrophic neurites in cortex and striatum. The presence of these fragments is thought to be associated with HD because the polyglutamine tract could produce the transition to aggregation form of HTT. The presence of oligomers and aggregates precedes large protein deposits. Several studies compared wild type and mutant HTT and they have reported an abnormal expression of mutant htt because it leads to the formation of cytoplasmic and nuclear inclusions. Polyglutamine tract length, time and huntingtin concentration determine amyloid-like htt aggregates.

 

Mutant HTT can develop unexpected functions such as binding abnormal factors and modifying their activity. It is also correlated to mitochondria dysfunction. This event results in oxidative stress, apoptosis, increased intracellular calcium and decreased energy production.