The I do, I do, I do of Huntington’s Chorea

Why do we have to say ‘I do’ 3 times when we take marriage vows? I don’t know. In the short arm of chromosome 4 (4p) too, there are such quizzical repeats. It contains enigmatic repeats of trinucleotide CAG (cytosine adenine guanine). These repeats are highly conserved, again it is not known why. Normally there are 11 to 34 of such trinucleotide repeats. It is known that codons usually give rise to amino acids through transcription and then translation. CAG sequence produce glutamine. Thus the result of these repeats is a polyglutamate residue. The product of this gene is a protein called huntingtin (Htt), a picture of which is shown on the left.

In Huntington’s disease, the number of such repeats increases from 37 to 86. The more the repeats, the more the severity of the disease and the earlier the onset. Huntington’s chorea is characterized by hyperkinetic features consisting of rapid, semipurposeful, involuntary, repetitive, unpatterned movements of parts of the body. In the beginning, one limb is involved which ultimately involves the whole body. It appears ass if the patient is dancing, chorea meaning dance. The sequences at exons of 4p also leads to neurodegenerative changes leading to severe dementia and ultimately death. In the middle to late stage of the disease, the caudate nucleus atrophies.

There is loss of GABAergic neurons emerging from the striatum and this causes excitatory symptoms. What causes the destruction of the neurons is unsettled. Abnormal huntingtin may accumulate within the cell and interfere with its metabolism. Recent studies demonstrate that abnormal huntingtin may translocate into the nucleus where it interferes with transcription regulating proteins. Whatever be the mechanism, the consequence is uniformly fatal.

The treatment is virtually non existent. Atypical antipsychotics like clozapine or quetiapine help to relieve dementia, while haloperidol, a dopamine receptor antagonist is somewhat useful in controlling the motor frenzy. Antioxidants, antiglutamates, antiapoptotic agents like caspase 1 inhibitors, inhibitors of aggregation, intracerebral infusion of neurotrophic factors, fetal striatal tissue transplantation and other avenues for combating this illness is desperately being sought. Its time to help them stop dancing.

Last modified: Oct1, 2008
Reference: John B. Penney, Jean-Paul Vonsattel, Marcy E. Macdonald, James F. Gusella, Richard H. Myers (1997). CAG repeat number governs the development rate of pathology in Huntington's disease

Neuronal Circuitry of Basal Ganglia

Located deep within the matters of the brain are a group of structures which plan and program, initiate, control and execute motor functions in a well coordinated manner. It is also involved in the maintenance of muscle tone. The Basal Ganglia comprises of the following structures:

Caudate nucleus
Putamen
Globus Pallidus
Substantia Nigra
Subthalamic nucleus (also known as the body of Luys)

Caudate nucleus and Putamen together are called corpus striatum; while Putamen and Globus pallidus together go by the name of lenticular nucleus. So much for the anatomy part. The way these nuclei communicate with each other, and with the brain and the spinal cord, is largely unknown. A probable wiring diagram, which is presently accepted (and quite complicated), is presented here. Red lines represent excitatory fibers; green lines inhibitory fibers.

Globus Pallidus interna (GPI), the internal segment of GP, secretes a chemical called gamma amino butyric acid or GABA for short. This is an inhibitory neurotransmitter, meaning that it will NOT allow neurons it supplies, to fire. As you can see, GPI inhibits PPN (pedunculo-pontine nucleus), the motor outflow to the brainstem and spinal cord. It also inhibits thalamus, which stimulates the brain through the thalamocortical circuit. Thus we see that GPI inhibits both the brain and the spinal cord.

Now see that GPI itself gets inhibitory fibers from the striatum directly, via obviously the direct pathway. It also gets glutaminergic (also called glutamatergic) stimulatory (excitatory) fibers from the sub-thalamic nucleus (STN). But STN itself is inhibited by GABAergic fibers arising from GPE (globus pallidus externa) which again is inhibited by fibers from the striatum. (to make matters light, it reminds me of “seventh son of a seventh son”—by Iron Maiden!). Hence the net result through the second pathway (indirect pathway) is excitatory. So the direct pathway inhibits, while indirect pathway stimulates the GPI. (step1) Picture on the left.

But the things are not so easy. The guy out there called substantia nigra pars compacta (SNPC) secretes dopamine (the reward chemical). This substance is secreted in the striatum. Now dopamine combines with its receptor (a receptor is like a lover longing to unite, but not ignite, as we lovers do!!). In the direct pathway, it combines D1 receptor and stimulates. But it combines with D2 receptors on the neurons of the indirect pathway, and inhibits its outflow. Thus dopamine in effect inhibits GPI. (step2)

So what do we see now? Dopamine inhibits GPI (step1), which inhibits both the brain and the spinal cord. (step2) Thus dopamine EXCITES the brain and the spinal cord. (The final result)

The above sequence operates normally. In Parkinsonism, the dopaminergic neurons die a slow death. As a result, the brain and spinal cord is inhibited and hypokinetic symptoms appear. Excitatory features like tremor are also present in Parkinsonism. Huntington’s chorea, another disease which involves this circuit, occurs due to destruction of GABA secreting neurons, as is shown in the adjoining picture. Notice the internuclear dopaminergic and intrastriatal cholinergic fibers. Hemiballismus (flailing movements of limbs) and athetosis (slow and writhing movements) are other manifestations of diseases of the basal ganglia.

Last modified: March 27, 2009
Reference: 1.William F Ganong, Review of medical physiology, 22nd ed., pp 213-217
2. Textbook of medical physiology, 11th ed., Guyton & Hall 707-712