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Sources: Nucifora FC Jr, et al. Interference by huntingtin and atrophin-1 with CBP-mediated transcription leading to cellular toxicity. Science. 2001;291:2423-2428; Steffan JS, et al. Huntingtin inhibits acetyltransferases and histone deacetylase inhibitors suppress in vivo pathogenesis. Nature. 2001; in press; The Huntington Study Group. A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease. Neurology. 2001;57:397-404.
In Huntington’s disease (HD), recent work has focused on the interaction of huntingtin with transcription factors. The genetic abnormality called huntingtin in HD is a CAG repeat expansion of more than 39 CAGs. Expanded polyglutamine domains in the mutant protein result in protein interactions, with other polyglutamine containing proteins by facilitating a "polar zipper" mechanism. Recent studies demonstrated that mutant huntingtin can interact directly with several transcription factors including P53, P300, and the transcription factor coactivator CREB-binding protein (CBP). In the presence of mutant huntingtin in cell culture, in transgenic HD mice, as well as in human postmortem brain tissues, CBP is depleted from its normal nuclear localization, and sequestered into huntingtin containing aggregates. This effect depends on the length of the polyglutamine repeat stretch. Furthermore, transcription assays have shown that expression of the growth factor, BDNF, is regulated by CBP, and it is downregulated in HD brain tissue. This provides further evidence that mutant huntingtin expression is detrimental to gene transcription. The importance of these interactions is underscored by observations that CBP function is similarly modulated by mutant polyglutamine repeats in other CAG repeat-expansion diseases, including spinobulbar muscular atrophy, spinocerebellar ataxia-3, and dentatorubropallidoluysin atrophy (DRPLA).
One means by which CBP modulates gene transcription is by acting as a histone acetylase. Accordingly, it sequestrates CBP into huntingtin aggregates which decreases histone acetylation, and reduces gene transcription. The histone acetylase activity of CBP is directly inhibited by mutant huntingtin. This raises the novel possibility that a therapy for HD may be to increase histone acetylation to ameliorate the illness. A number of compounds have been developed that are histone deacetylase inhibitors. These agents were developed for the treatment of cancer, since they induce the differentiation of cancer cells, causing increased vulnerability to cancer chemotherapy. Initial studies have shown efficacy of these compounds in cell culture models of HD, as well as a drosophila model. A tantalizing approach, therefore, is to use these agents as a novel therapy for HD.
A downstream consequence of the impaired transcriptional regulation in HD may be defective energy metabolism. We and others used magnetic resonance spectroscopy to establish that there are elevations of lactate in the basal ganglia, and reductions in phosphocreatine and ATP levels in the skeletal muscle of Huntington’s patients, including patients at risk. In view of this, we investigated whether agents that may modulate energy metabolism could have therapeutic efficacy. A recent trial studied the effects of coenzyme Q10, an energy modulator, and remacemide, an NMDA excitatory amino acid antagonist. The results showed that coenzyme Q10 administration slowed disease progression by 13%, while remacemide had no effects. Although remacemide provided efficacy in mice, the dose used was intolerable in humans. We also investigated whether oral administration of creatine, which can increase brain phosphocreatine levels, exerts neuroprotective effects. Our studies have shown significant neuroprotective effects in transgenic mouse models of both ALS and HD (Ferrante RJ, et al. J Neurosci. 2000;20:4389-4397). Clinical trials to determine whether these agents will have efficacy in man are either being planned or underway. Initial studies using neurotransplantation in HD have shown limited improvement and that the grafts survive. Although symptomatic treatment with dopamine receptor antagonists exerts some effects on chorea, most patients prefer to avoid the side effects of these medications. —Flint Beal
Sources: McNaught KSP, et al. Failure of the ubiquitin proteasome system in Parkinson’s disease. Nat Rev Neuroscience. 2001;2:589-594; Shimura H, et al. Ubiquitination of a new form of alpha-synuclein by parkin from human brain: Implications for Parkinson’s disease. Science. 2001;293:224-225; Beal MF. Experimental models of Parkinson’s disease. Nat Rev Neurosci. 2001;2:325-334; Glasson BI, et al. Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synuclienopathy lesions. Science. 2001; 291:595-597.
In Parkinson’s disease (PD), major advances have come from the finding of 2 associated separate genetic defects associated with the illness. Autosomal dominant inherited PD has been associated with mutations in the protein a-synuclein. Autosomal recessive early onset PD has been associated with mutations in a protein termed parkin. It has been demonstrated that a-synuclein is a major component of lewy bodies, the pathologic hallmark of PD. It is, therefore, theorized that abnormal aggregation of this protein may directly contribute to the disease pathogenesis. It is thought that aggregated protein may prevent normal degradation, thereby contributing to cellular stress. The parkin protein has been demonstrated to be a ubiquitin ligase (E3). Ubiquitin conjugation to damaged proteins is essential for their degradation by the proteasome. It is, therefore, theorized that the parkin mutation, which impairs the normal functioning of ubiquitin ligase enzymatic activity, may lead to accumulation of abnormal proteins. Recently it has been demonstrated that one of the substrates of parkin is a 22-kDa glycosylated form of a-synuclein referred to as a-SP22. It appears that the familial PD-related mutations in parkin reduce the polyubiquitination of proteins such as a-SP22, which has been shown to accumulate in a non-ubiqutinated form in dopamine neurons in the substantia nigra compacta of juvenile onset PD patients. In transgenic mouse models of ALS, there is also increasing evidence that aggregates of mutated Cu/Zn superoxide dismutase may play a critical role. Recent evidence suggests that abnormal catalytic activity of Cu/Zn superoxide dismutase is less likely to be important since removing the catalytic copper does not have an effect on disease progression.
Also, substantial evidence demonstrates impairments of mitochondrial complex I activity in the substantia nigra of PD. Interestingly, systemic administration of the specific complex I inhibitor rotenone produces selective degeneration of substantia nigra neurons. It produces cytoplasmic inclusions that have the characteristic appearance of lewy bodies, and stain with a-synuclein and ubiquitin. Other studies have shown that administration of the neurotoxin MPTP can also upregulate the expression of a-synuclein. Possibly, these metabolic defects could contribute to the generation of lewy bodies by upregulating a-synuclein expression, and also by inducing oxidative stress. Lewy bodies in human PD are oxidatively modified and stained with antibodies raised against nitrated a-synuclein. Nitration is a characteristic feature of oxidative damage mediated by peroxynitrite.
A major NIH funded initiative to investigate neuroprotective treatments in PD has recently been announced. Ongoing trials are evaluating neuroprotective effects of monoamine oxidase b inhibitors, riluzole, and coenzyme Q10. Many other agents targeted at oxidative damage, growth factors, or apoptotic cell death appear promising in animal studies. Lastly, both PD and ALS are primary targets for replacement therapy using neuronal stem cells. —Flint Beal
Dr. Beal is Chairman of Neurology and Neuroscience, Cornell Medical Center, New York Presbyterian Hospital, New York, NY.