Review 1 Central & Peripheral Nervous Systems Huntington’s disease: progress 5 and potential in the fi eld † Edward C Stack & Robert J Ferrante 1. Background † Boston University School of Medicine , Departments of Neurology , Pathology, and Psychiatry, 2. Existing clinical Edith Nourse Rogers Veterans Administration Medical Center , Experimental Neuropathology Unit 10 management and need and Translational Therapeutics Laboratory , GRECC Unit, Building 18 , 3. Mechanisms of cell death and Bedford, MA 01730 , USA potential therapeutic targets in Huntington’s disease While the first description of Huntington’s disease was reported over a century ago, no therapy exists that can halt or ameliorate the inexorable 4. Therapeutic candidates 15 disease progression. Tremendous progress, however, has been made in 5. Conclusion significantly broadening the understanding of pathogenic mechanisms in 6. Expert opinion this neurological disorder that may eventually lead to successful treatment strategies. Huntington’s disease is caused by the expansion of a CAG repeat in the huntingtin gene, which results in the expression of a mutant form 20 of the protein that is toxic to neurons. Several mechanisms have been iden- tified in mediating this toxicity, such as protein aggregation, mitochondrial dysfunction, oxidative stress, transcriptional dysregulation, aberrant apop- tosis, altered proteosomal function and excitotoxicity. With increasing understanding of each of these pathogenic mechanisms, therapeutic 25 strategies have attempted to target specific aspects of each. There have been many encouraging reports of preclinical efficacy in transgenic Huntington’s disease mice, from which a number have been extended to human clinical trials with some success. This review focuses on these studies and the compounds that hold promise for treating human 30 Huntington’s disease. Keywords: apoptosis , excitotoxicity , mitochondria , oxidative stress , transcription , ubiquitin-proteosome system 35 Expert Opin. Investig. Drugs (2007) 16(12):1-21 1. Background Huntington’s disease (HD) is an inherited autosomal dominant disorder of 40 the CNS. Roughly 250,000 Americans are affected by or are at risk of inheriting this fatal disease. Clinically, HD is characterized by cognitive and memory impairments, heightened irritability, depression, weight loss and choreic motor abnormalities [1] . Interestingly, subtle behavioral alterations occur prior to clinical diagnosis [2,3] , consistent with evidence of altered neuropathology before manifest 45 disease [4] . Once manifest disease occurs, however, the duration of HD is ∼ 15 – 20 years, with clinical symptoms becoming increasingly disabling prior to death [1] . Despite great progress, a direct causative pathway from the HD gene mutation to neuronal death has not yet been established. As there is no proven therapy to delay or slow the progression of HD, there is a growing demand on 50 improved clinical management for affected individuals and their families. While other brain regions are altered in HD, the most prominent neuro- pathological feature is marked gross atrophy of the neostriatum with concomitant neuronal degeneration within the caudate and putamen. There is a topographic progression of neuronal loss and astrogliosis first observed in the dorso-medial 55 aspect of the striatum and progressing ventro-laterally, with relative sparing of the 10.1517/13543784.16.12.1 © 2007 Informa UK Ltd ISSN 1354-3784 1 Huntington’s disease: progress and potential in the fi eld 1 ventral striatum [5] . Not all neurons are affected equally inhibitors sertraline and fluoxetine and/or benzodiazepines, within the neostriatum [6] . While large cholinergic neurons such as clonazepam, diazepam, risperidone or sulpiride [26] . and medium-sized NADPH-diaphorase aspiny neurons There is no significant evidence that any given antipsychotic remain relatively spared in HD, medium-sized spiny drug is better than another in the treatment of symptoms. 5 GABAergic projection neurons of the striatum, which make up ∼ 95% of striatal neuron content, are disproportionately 3. Mechanisms of cell death and potential affected early and most severely [6-9] . There is also a reduc- therapeutic targets in Huntington’s disease tion in striatal neurochemicals that parallels striatal neuro- degeneration in HD [10,11] , with substance P-expressing striatal 3.1 Mutant Huntingtin aggregation (mHtt) 10 projection neurons appearing more vulnerable [12] . In While the gene responsible for HD was discovered almost addition, striatal medium spiny neurons show both 15 years ago [15] , the relationship between mHtt and the proliferative and degenerative changes leading to neuronal multiple molecular pathways that appear to mediate neuronal dysfunction and cell death [13,14] . death in HD is still not well understood. Transglutaminase HD is caused by an expanded trinucleotide CAG repeat activity has been proposed to mediate mHtt aggregation [27] . 15 in the gene coding for the protein, huntingtin (Htt) [15] . There is ample evidence regarding transglutaminase In HD patients, the CAG repeat is expanded beyond expression in HD [28-30] and a role for transglutaminase the normal repeat range, > 38 repeats, with an inverse in HD pathogenesis is now well accepted. relationship between the CAG repeat number and the age of Interestingly, proteins containing polyglutamine expansions, onset, with higher repeats associated with younger age [16] . such as mHtt, are degraded in a limited context by the 20 Expression of Htt is observed throughout the brain within the ubiquitin–proteosome system (UPS) [31] . However, recent nucleus, cytoplasm, axons and dendrites of neurons [17-19] . data suggests that the proteosome may not cleave polygluta- While the function of normal Htt is not known, it is mine sequences within the mutant protein [31] . Ongoing thought to play a role in cellular transport mechanisms [17,20] . debate continues, as with other neurodegenerative disorders Cleaved during proteolysis, mutant Htt (mHtt) releases a in which protein aggregates are a hallmark of disease, 25 persistent N-terminal fragment that contains the expanded questioning whether inclusions formed by the aggregated polyglutamine amino acid sequence. This fragment, which is N-terminal truncation of mHtt cause neuronal death believed to confer toxicity, forms aggregates with itself and through alterations of nuclear transport or DNA arrange- other proteins seen in both the cytoplasm and nucleus [18] . ments affecting transcription. Recent studies have suggested The aberrant protein interactions of mHtt and formation a protective role for aggregation [19,32,33] . Through the use of 30 of mHtt aggregates may lead to neuronal toxicity through an automated microscopy technique to assess the time frame a toxic gain of function mechanism. Observations where in which neurons expressing mHtt expire, improved survival nuclear aggregates have been seen in interneuron of neurons that contained mHtt aggregates has been populations known to be resistant to HD-induced shown [32] . Whether the formation of mHtt aggregates is neurodegeneration [19] , suggest that soluble mHtt is the protective or toxic, it is clear that coincident with mHtt 35 harbinger of neurodegeneration. In contrast, additional aggregation, there are additional pathogenic cascades at evidence suggests that the aggregated form of mHtt is toxic work in HD. and can induce neurodegeneration [21] . 3.2 Oxidative stress and mitochondrial dysfunction 2. Existing clinical management and need Several lines of evidence lend support for mitochondrial 40 dysfunction and increased oxidative stress in HD [34] . There Existing care in HD is focused primarily on symptom is a general reduction in striatal glucose utilization in both management. As such, a number of drug agents have been human and transgenic mouse HD brain that precedes tissue used to treat the motor and behavioral changes found in loss [35,36] , as well as a reduction in the activity of several HD. Both amantadine [22] and memantine [23] , glutamatergic mitochondrial complexes [37,38] . Lactate levels are elevated in 45 N -methyl-D-aspartate (NMDA) antagonists, have been used the striatum and cortex, with the increase correlated with to treat chorea. While haloperidol has also been used in the the CAG repeat size [39] . Biomarkers of oxidative stress are management of dystonia and psychosis in HD, treatment is also elevated in human and transgenic mouse HD brain and complicated by extrapyramidal side effects [24] . More recent serum, such as DNA oxidative modifications and strand data regarding the type 2 vesicular monoamine transporter breaks [40-42] and deletions in mitochondrial DNA [43] . 50 inhibitor, tetrabenezine, which selectively blocks dopamine Recent evidence suggests that mHtt interacts directly release, demonstrates significant improvement in chorea with mitochondria in HD [44] . This interaction causes an in ambulatory HD patients [25] . Clinical practice in HD alteration in mitochondrial calcium buffering, leading to also employs a number of antipsychotic agents for the mitochondrial dysfunction. In addition, it has been reported management of depression, anxiety and other psychiatric that mHtt represses peroxisome proliferator-activated 55 disturbances. These include the selective serotonin uptake receptor-γ co-activator 1α (PGC-1α ) [45] . PGC-1α is a 2 Expert Opin. Investig. Drugs (2007) 16(12) Stack & Ferrante 1 transcriptional co-activator regulating a number of genes