Neural tissue transplanted into the brains of three Huntington’s patients mostly degenerated within a decade, despite initially producing modest signs of improvement, according to a new study. The finding is consistent with other recent studies suggesting that neurodegenerative diseases may spread, in effect, even to transplanted neural tissue.
“The grafted cells degenerated much faster than those of the host,” says study lead author Francesca Cicchetti, a neurodegenerative disease researcher at the University of Laval in Quebec City. “They also were undergoing degeneration processes which resembled those of the host.”
Huntington’s is a fatal inherited disease in which a mutant gene, HTT, has internal DNA sequences that code for an excessively long chain of glutamine amino acids. Precisely how the resulting polyglutamine-laden protein kills neurons remains a mystery, but researchers know that it eventually overcomes the brain’s protective mechanisms, so that by early adulthood to middle age, initial disease signs appear.
The most prominent of these are spasmodic, uncontrollable movements, apparently caused by the destruction of medium spiny neurons and other cells in the striatum region of the brain. Spiny neurons connect with cortical neurons that release the excitatory neurotransmitter glutamate, and glutamate “excitotoxicity” has been one proposed mechanism of destruction in Huntington’s.
In early experiments with animal models of Huntington’s, transplants of healthy fetal brain tissue into the striatum produced a modest relief of disease signs. Thus, in the late 1990s, a team led by neurosurgeon Thomas Freeman at the University of South Florida, and Cicchetti, then a postdoctoral student at Harvard, began a transplant trial in seven human patients.
In 2000 the team published an analysis of the brain of one of these patients, who had died of heart disease 18 months after the transplant. A significant amount of transplanted tissue had not only survived but had become partly integrated within the brain, the researchers found. And clinical evaluations of this patient and some of the others suggested that the disease had at least stopped getting worse. Freeman and his colleagues concluded then that “implanted fetal neural cells lacking the mutant gene may be able to replace damaged host neurons and reconstitute damaged neuronal connections.”
But follow-up studies found that the clinical benefits did not last more than a few years, and recently, three more of these transplant recipients died, all of complications from the disease. In the new paper, which appeared online on July 20 in the Proceedings of the National Academy of Sciences, Ciccheti, Freeman and colleagues report that the transplants had largely degenerated by the time of these patients’ deaths.
The researchers aren’t yet sure what caused the demise of the transplanted cells, but they suspect that the disease process itself played a role. Analysis revealed that transplanted medium spiny striatal neurons bore the brunt of the degeneration, a process also seen in untreated Huntington’s. The researchers also noted some signs of inflammation, which might also have contributed to the damage.
Ciccheti says that she hopes to follow up with further transplant experiments in animals, perhaps at earlier stages of the disease when the host brain is less hostile to transplanted tissue, and with other, possibly more efficient transplant methods.
The possibility that degeneration effectively can spread from host cells to transplanted cells is currently being looked at for other neurodegenerative conditions. In one recent case, for instance, a research group that included Freeman found that fetal cells transplanted into the brains of Parkinson’s patients sometimes developed clumps of an abnormally-folded protein, alpha-synuclein, like those seen in diseased cells.
Other researchers have shown in cell culture experiments that misfolded alpha-synuclein can spread to healthy cells, which then begin to show signs of serious damage. French researchers also have described the infection-like spread, within mouse brains, of a pathological form of the Alzheimer’s-associated protein tau. Yet another recent report details the cell-to-cell spread of abnormal polyglutamine aggregates similar to those found in Huntington’s-affected cells.
Cicchetti and colleagues didn’t find aggregates of abnormal HTT protein in the transplanted grafts—which had largely disappeared anyway. But they did note the presence of such aggregates in a part of the cortex where the glutamine-releasing, potentially toxic connections originate. “We didn’t pursue it further, but this is obviously something that needs more research,” she says.
Eliezer Masliah, a neuropathologist at the University of California, San Diego, who co-wrote the spreading alpha-synuclein study, finds the study by Cicchetti and colleagues broadly consistent with the idea that neurodegeneration can spread via abnormal proteins.
“Even proteins that accumulate primarily within cells, such as HTT and alpha-synuclein, under pathological conditions can be secreted and damage adjacent neurons and grafts,” he notes. Neural tissue transplantation may yet develop into a viable treatment strategy for disorders such as Huntington’s and Parkinson’s, Masliah adds—but to confer long-term benefits, such transplants may have to be engineered specifically to resist the toxic processes at work in their new hosts.