By: Lise Munsie, PhD
In the lab. . .
Future clinical treatments for HD are likely to vary from patient to patient and involve multiple therapies to address all symptoms of the disease. Investigators are seeking to find novel ways to assess HD pathology, and they continue to research the molecular mechanisms of HD.
Sathasivam and colleagues describe aberrant splicing of Htt that leads to mRNA translation of an Htt exon1 fragment in the presence of the expanded polyglutamine tract1 that is characteristic of mHtt. Their results suggest that mHtt may be present at exon1 as a result of direct translation, not proteolytic cleavage.
Steinert and colleagues used a drosophila larva neuromuscular junction model to investigate glutamatergic synaptic transmission in HD2. Their manuscript describes vesicle defects in the presence of exon1 mHtt and reports that an overexpression of Rab11 at the endosomal recycling system rescues both synaptic and behavioral defects in this model.
Previous work has implicated the Rhes protein with the progression of HD. Rhes protein is a GTP binding protein enriched in the striatum. Baiamonte and colleagues crossed Rhes knockout mice with the R6/1 HD mouse model to study the effects of Rhes on the progression of HD3. The cross resulted in a delay in the behavioral symptoms of HD.
Lu and Palacino created a human neuronal model of HD4. Overexpressed Htt exon1 fragments recapitulated disease by causing protein aggregation and neurodegeneration in a neuronal population derived from induced pluripotent stem cells. The authors’ results support previously published data that suggests that soluble mHtt is a main toxic species.
In transition. . .
Promising pre-clinical data has emerged in the field of HD research.
Methylene blue, previously tested in Alzheimer’s disease, shows therapeutic potential in HD and is being tested for efficacy in HD readouts by a group at the University of California, Irvine. Sontag and colleagues report that methylene blue can inhibit the in vitro aggregation of mHtt and can also lead to functional improvements in the drosophila and R6/2 mouse models of HD5.
Human samples acquired by the TRACK-HD study have been used to develop an assay that detects levels of Htt in peripheral immune cells. Weiss and colleagues report the use of time-resolved Förster resonance energy transfer to quantify both total Htt and mHtt levels6. The assay detects differences in mHtt levels in different leukocyte populations. This study also reports that mHtt levels in monocytes were associated with rates of caudate and whole brain atrophy and ventricular expansion. Sawiak and colleagues created a public database of their ex vivo brain imaging from cohorts of both R6/2 and YAC128 HD mouse models7. Almost 400 datasets containing structural data and tissue maps for each individual brain are available. As in vivo data is obtained it will be added to this free online resource. Datasets may be accessed at http://dspace.cam.ac.uk/ handle/1810/243361 and may be viewed using online freeware. Medical imaging is at the forefront of biomarker research in HD. The availability of large datasets will aid investigators to make correlations between mouse models of HD and human brain imaging being undertaken for studies in neurodegenerative disease.
In the clinic. . .
A variety of therapeutic approaches are entering clinical trials for HD.
The drug PBT2, developed by Prana Biotechnology Ltd, has shown to improve cognition in Alzheimer’s disease8 and is now also a clinical trial candidate for HD. PBT2 is an 8-hydroxyquinoline analog that has affinity for transition metals, and may be able to liberate metals that contribute to pathology in HD. In a recent PloS One publication9, investigators report the alleviation of symptoms in a Caenorhabditis elegans model of aggregation, and the improvement of motor symptoms and a decrease in striatal atrophy in the R6/2 mouse model of HD, in response to PBT2. A phase II study of PBT2 for patients with early to mid-stage HD is ongoing10.
The ‘NEST-UK’ consortium at the University of Cambridge recently reported on the safety of using fetal striatal cell transplants to repair damaged cells in the striatum of HD patients11. Transplants were performed in five patients with mild HD symptoms and postoperative follow-up continued for up to 10 years. This follow-up was unable to detect any significant changes in either the Unified Huntington’s Disease Rating Scale or the Mini-Mental State Examination. However, this study does prove the safety of the protocol and lays the foundation for larger-scale studies of this intervention. Case reports have also featured the benefits and side effects of deep brain stimulation for HD12. Deep brain stimulation has been moderately successful for HD motor symptoms and has been shown to be safe for HD patients.
1 Sathasivam K, Neueder A, Gipson TA, et al. Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease. Proceedings of the National Academy of Sciences of the United States of America 2013 Feb; 110(6):2366-70.
2 Steinert JR, Campesan S, Richards P, et al. Rab11 rescues synaptic dysfunction and behavioural deficits in a Drosophila model of Huntington’s disease. Human molecular genetics 2012 Jul; 21(13): 2912-22.
3 Baiamonte BA, Lee FA, Brewer ST, et al. Attenuation of Rhes activity significantly delays the appearance of behavioral symptoms in a mouse model of Huntington’s disease. PloS one 2013; 8(1):e53606.
4 Lu B, Palacino J. A novel human embryonic stem cell-derived Huntington’s disease neuronal model exhibits mutant huntingtin (mHTT) aggregates and soluble mHTT-dependent neurodegeneration. FASEB journal 2013 Jan.
5 Sontag EM, Lotz GP, Agrawal N, et al. Methylene blue modulates huntingtin aggregation intermediates and is protective in Huntington’s disease models. The Journal of Neuroscience 2012 Aug; 32(32):11109-19.
6 Weiss A, Trager U, Wild EJ, et al. Mutant huntingtin fragmentation in immune cells tracks Huntington’s disease progression. The Journal of Clinical Investigation 2012 Oct; 122(10): 3731-6.
7 Sawiak SJ, Wood NI, Carpenter TA, Morton AJ. Huntington’s disease mouse models online: high-resolution MRI images with stereotaxic templates for computational neuroanatomy. PloS one 2012; 7(12):e53361.
8 Faux NG, Ritchie CW, Gunn A, et al. PBT2 rapidly improves cognition in Alzheimer’s Disease: additional phase II analyses. J Alzheimers Dis 2010;20(2):509-16.
9 Cherny RA, Ayton S, Finkelstein DI, et al. PBT2 Reduces toxicity in a C. elegans model of polyQ aggregation and extends lifespan, reduces striatal atrophy and improves motor performance in the R6/2 mouse model of Huntington’s disease. J Huntington’s Dis 2012;1(2):211-9.
10 http://clinicaltrials.gov/ct2/show/NCT01590888? term=reach2hd&rank=1
11 Barker RA, Mason SL, Harrower TP, et al. The long-term safety and efficacy of bilateral transplantation of human fetal striatal tissue in patients with mild to moderate Huntington’s disease. J Neurol Neurosurg Psychiatry 2013 Jan.
12 Velez-Lago FM, Thompson A, Oyama G, et al. Differential and better response to deep brain stimulation of chorea compared to dystonia in Huntington’s disease. Stereotact Funct Neurosurg 2013 Jan; 91(2):129-33.