Neural transplants in patients with Huntington's disease undergo disease-like neuronal degeneration
Document Type
Article
Abstract
The clinical evaluation of neural transplantation as a potential treatment for Huntington's disease (HD) was initiated in an attempt to replace lost neurons and improve patient outcomes. Two of 3 patients with HD reported here, who underwent neural transplantation containing striatal anlagen in the striatum a decade earlier, have demonstrated marginal and transient clinical benefits. Their brains were evaluated immunohistochemically and with electron microscopy for markers of projection neurons and interneurons, inflammatory cells, abnormal huntingtin protein, and host-derived connectivity. Surviving grafts were identified bilaterally in 2 of the subjects and displayed classic striatal projection neurons and interneurons. Genetic markers of HD were not expressed within the graft. Here we report in patients with HD that (i) graft survival is attenuated long-term; (ii) grafts undergo disease-like neuronal degeneration with a preferential loss of projection neurons in comparison to interneurons; (iii) immunologically unrelated cells degenerate more rapidly than the patient's neurons, particularly the projection neuron subtype; (iv) graft survival is attenuated in the caudate in comparison to the putamen in HD; (v) glutamatergic cortical neurons project to transplanted striatal neurons; and (vi) microglial inflammatory changes in the grafts specifically target the neuronal components of the grafts. These results, when combined, raise uncertainty about this potential therapeutic approach for the treatment of HD. However, these observations provide new opportunities to investigate the underlying mechanisms involved in HD, as well as to explore additional therapeutic paradigms.
Keywords
Excitotoxicity, Glutamate, Inflammation, Microglia, Mutant huntingtin
Publication Date
7-28-2009
Publication Title
Proceedings of the National Academy of Sciences of the United States of America
ISSN
00278424
E-ISSN
10916490
Volume
106
Issue
30
First Page
12483
Last Page
12488
PubMed ID
19620721
Digital Object Identifier (DOI)
10.1073/pnas.0904239106
Recommended Citation
Cicchetti, F.; Saporta, S.; Hauser, R. A.; Parent, M.; Saint-Pierre, M.; Sanberg, P. R.; Li, X. J.; Parker, J. R.; Chu, Y.; Mufson, E. J.; Kordower, J. H.; and Freeman, T. B., "Neural transplants in patients with Huntington's disease undergo disease-like neuronal degeneration" (2009). Translational Neuroscience. 1890.
https://scholar.barrowneuro.org/neurobiology/1890