. Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines. Nat Neurosci. 2002 Aug;5(8):731-6. PubMed.


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  1. The paper by Panov et al. is absolutely timely. We knew that the mitochondria were involved in HD. We had beautiful evidence that, i.e. animals exposed to systemic injection of a mitochondrial toxin (3-nitropropionic acid) were reproducing neurological deficits similar to those present in HD. However, this evidence was indirect. In other words, we were supposing that 3NP was evoking striatal toxicity by acting along the same pathway(s) or on the same targets as did mutant huntingtin. But we did not know where the precise link was.

    Now this paper shows that mutant but not wild-type huntingtin binds to the mitochondria, whose critical roles in living cells include ATP production, handling calcium, and controlling the activity of specific and potentially harmful enzymes. By binding to mitochondria, mutant huntingtin impairs its functionality, leaving cells in the middle of an earthquake. Changes in calcium homeostasis can activate proteases like the calpains, which cleave other proteins including wild-type huntingtin itself, which we found to be neuroprotective. This double whammy of a toxic mutant protein and loss of function of the wild-type huntingtin leads to disease.

    Panov et al. have beautifully confirmed their studies in three experimental settings, first, after incubation of purified normal mitochondria with mutant huntingtin, second, by analyzing the activity of these organelles isolated from control and transgenic mice overexpressing mutant huntingtin, and third, by studying the mitochondria from lymphoblasts of HD patients.

    Two questions remain unsolved: how can the disease remain latent for approximately the first 35 years of life, and how does the observed dysfunction of the mitochondria cause the selective striatal vulnerability in HD? In their paper the authors show that the mitochondrial dysfunction precedes by months symptom manifestation in mice. Therefore, it may well be that disease onset, as defined clinically, is actually preceded by subtle dysfunctions that accumulate for years and, slowly but relentlessly, bring the individual to a stage when these abnormalities cannot be hidden anymore.

    On the second question, the situation is equally mysterious. As expected, the Panov paper contains no indication that mutant huntingtin binds preferentially to striatal mitochondria, as indeed lymphoblast mitochondria show the same defect. The mutant protein may hamper the activity of several cell types, if not all, but the striatal mitochondria may be more disturbed by their inability to handle calcium properly. The striatum receives an important and specific afferent pathway from the cerebral cortex that releases the potent excitotoxin glutamate. Various data indicate a hyperactivity of this pathway in HD. Altered mitochondrial calcium handling in striatal HD neurons may render neurons unable to process the cortical glutamatergic input correctly.

    It could also be that mitochondrial dysfunction is not the trigger but a consequence of other cellular abnormalities. At this stage of research, any possibility should be taken seriously until we have established a temporal pattern for the various interesting cellular dysfunctions reported by several authors. Among them is the loss of normal huntingtin activity, which also may produce a striatal defect.

    Thorough investigations of disease mechanisms and cooperation between basic and clinical science is necessary if we are to give hopes to those that suffer from Huntington's disease.

    View all comments by Elena Cattaneo

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