Of particular interest is the role of the proteases family calpain in HD. (Proteases chop up proteins.) An early research paper by the distinguished researcher Roos suggested that milk could shorten the time to the onset of symptoms. Unfortunetly there was a lot of emotional critisism and no follow up studies. Eventually it was found that calpain is elevated in HD patients. Calpain has something to do with milk. The effect of calpain on exercise induced muscle cell damage is worsened by the casein, found in cow's milk, and lessened by soy, found in soy milk. See: Soy Benefit.

The following article presents a 'best evidence' look at the effects of the expanded HD gene.

• HD is triggered. That is the onset and progression are by two different mechanisms. The practical consequence is that HD duration is independent of CAG count and perhaps huntingtin.
• Classical apoptosis or programmed cell death does not have a role.
• The turnover of the huntingtin protein is by calpain action, not by caspases as previously thought. The proposed mechanism of the action of minocycline as a caspase inhibitor to treat HD is wrong.
• The mechanism of HD may result from a defense mechanism against ischemia. See: Unexpected Huntington's Disease Finding . (In contrast to the following study.)
• Neuron injury results from the action of calpain on full length huntingtin protein.

Calpain degrades huntingtin "Calpain activation and huntingtin regulation merit investigation as modifiers of disease progression in neurons injured by the harmful consequences of full-length mutant huntingtin.", Marcy MacDonald, HD researcher.

Huntington's disease, with its dominant loss of striatal neurons, is triggered by an expanded glutamine tract in huntingtin.

To investigate a proposed role for increased activation of the apoptotic cascade in mutant huntingtin's trigger mechanism, we examined huntingtin cleavage and lesion severity after mild ischemic injury in Hdh(Q92) mice.

We found activation of calpain and caspase proteases and proteolysis of huntingtin in lesioned striatum. However, huntingtin fragments resembled products of calpain-1, not caspase-3, cleavage and turnover was accompanied by augmented levels of full-length normal and mutant protein. By contrast, the number of apoptotic cells, total and striatal infarct size, and degree of neurologic deficit were similar in Hdh(Q92) and wild-type mice, indicating that the disease process neither strongly protected nor sensitized striatal neurons to apoptotic death.

Thus, our findings do not support a role for increased apoptosis or caspase-3 cleavage in the mechanism by which mutant huntingtin triggers disease. However, they suggest that calpain activation and huntingtin regulation merit investigation as modifiers of disease progression in neurons injured by the harmful consequences of full-length mutant huntingtin.

Source: Neurobiol Dis 2002 Oct;11(1):147-54

	Read the HDAC/HDLighthouse Forum. Post your comments