Subscribe to eTOC

In the Pipeline-Movement Disorders
Tau Appears to Spread into Fetal Grafts in Huntington's and Parkinson's Brains

ARTICLE IN BRIEF

Finding tau pathology in postmortem neural grafts from patients with Huntington's disease and Parkinson's disease, researchers said the evidence strengthens the case that tau pathology contributes to the two diseases beyond the limited number of patients receiving therapeutic transplants. Independent experts were intrigued by the finding that the tau may spread in a prion-like way, but questioned whether tau pathology was specific to these two disorders.

Tau pathology develops in engrafted fetal cells in both Huntington's disease (HD) and Parkinson's disease (PD) patients who receive them, according to a November 1 study in Brain.

The finding adds tau to the list of misfolded proteins found in healthy cells grafted into a diseased brain and suggests that, like alpha-synuclein and huntingtin, pathologic tau may spread from the host to the graft.

It also strengthens the case that tau pathology contributes to the two diseases beyond the limited number of patients receiving therapeutic transplants, suggesting tau may be a candidate for therapy in a broad group of neurodegenerative diseases.

“We are adding to the growing body of evidence that tau pathology is present in both Huntington's disease and Parkinson's disease,” said lead study author Francesca Cicchetti, PhD, professor of medicine at Université Laval in Quebec, Canada. “We cannot overlook it anymore.”

Several hundred PD patients and about 50 HD patients have received grafts, though enthusiasm for either procedure has waned; in PD, because of problematic side effects, and in HD, because of lack of significant clinical benefit. Nonetheless, a new grafting trial in PD — TRANSEURO Open Label Transplant Study in Parkinson's Disease — is underway in Europe, and one in HD — Multicentric Intracerebral Grafting in Huntington's Disease — has just been completed, also in Europe.

FU1-11

DR. FRANCESCA CICCHETTI: “I think there are two distinct messages from our study. The first is that we believe that tau protein can propagate within the brain, targeting healthy cells and contributing to disease progression...The second message is that tauopathy is a feature of Huntington's disease and Parkinson's disease beyond the special cases of those who received grafts.”

THE RATIONALE FOR THE STUDY

The new study builds on several previous findings on the fate of transplanted fetal tissues in both diseases. In 2008, autopsies of multiple PD patients showed that grafted fetal tissue developed Lewy bodies as soon as ten years after transplantation; additional studies since then demonstrated the likelihood that misfolded host alpha-synuclein spread, prion-like, to the grafted tissue to induce misfolding there.

In 2014, Dr. Cicchetti and colleagues showed that mutant huntingtin could be found in transplanted tissue in HD patients. Since the only possible source of mutant protein was the host brain, it suggested that the protein could be transported from the host to the healthy grafted tissue, perhaps in a prion-like fashion in that disease as well. Recently, tau pathology — one of the hallmarks of Alzheimer's disease — has been seen in both HD and PD brains, and some evidence has suggested it may spread between neurons, at least in transgenic mice. That all led Dr. Cicchetti to ask whether tau could also be seen in fetal grafts in one or both diseases.

STUDY DESIGN

The investigators examined brains from two sporadic PD patients and two HD patients, as well as three non-neurologic controls. Patient brains were removed within two to 14 hours of death and then preserved. Regions both within and beyond the graft were then stained with a variety of antibodies to various forms of tau, covering the several different phosphorylation states in which the protein can exist.

Tau is normally phosphorylated to some extent, but hyperphosphorylation is associated with the diseased state, setting the stage for misfolding and aggregation. In the HD brains, nine years after transplantation in one, and 12 years post-transplantation in the other, hyperphosphorylated tau was identified in the grafted tissue, forming neurofibrillary tangles, neuropil threads, and inclusions.

Tau protein contains either three or four microtubule-binding domains. Healthy brain tissue contains equal amounts of the two forms, while an excess of the “four-repeat” versus the “three-repeat” form is associated with aggregation. While there was too little tissue to analyze the 4R/3R ratio in one brain, in the other, there was an increase in the 4R form compared to controls, not only in the host tissue, as expected, but also in the graft tissue. This suggests “that the transplant may have acquired tau pathology from the host brain,” Dr. Cicchetti said.

Similar pathology was seen in host tissue in both PD brains. It was also seen in the grafted tissue in one brain, 16 years post-transplantation, but not in the other, which was only 18 months post-transplantation, indicating there is “likely a time-related effect,” she said, with the tau pathology appearing progressively after transplantation.

And the effect is not likely just a matter of the graft aging in place, she noted. Examination of the three control brains showed that tau inclusions were absent in the brain of a 12-year-old, and extremely sparse in that of a 40-year-old, while they were more common in that of a 70-year-old, all of which suggests that the development of tau pathology in the grafts was accelerated in the diseased brain.

“I think there are two distinct messages from our study,” Dr. Cicchetti said. “The first is that we believe that tau protein can propagate within the brain, targeting healthy cells and contributing to disease progression.” The evidence is strong, but not ironclad, she said.

“Our analyses were performed on postmortem tissue,” she said, “therefore we speculate that the tau protein that we observed in the grafted tissue originates from transynaptic transport from the host, but we have not proven that.”

“The second message is that tauopathy is a feature of Huntington's disease and Parkinson's disease beyond the special cases of those who received grafts,” she continued. “The finding in this study, that in all cases the host brain contained tau pathology at levels greater than controls, supports other recent work confirming the presence of significant tau aggregation in both HD and PD.”

The conclusion, Dr. Cicchetti said, “is that the development of therapies may need to include targeting tau pathology in these disorders as well.”

EXPERT COMMENTARY

Commenting on the study, Marc Diamond, MD, professor of neurology and neurotherapeutics, and director of the Center for Alzheimer's and Neurodegenerative Diseases at University of Texas Southwestern in Dallas, said: “It is unknown whether the observed tau pathology has propagated into the graft, or arisen spontaneously. The only way to know would be to engraft neurons that lack tau, and see if they develop pathology.” That has been done for alpha-synuclein, he added, and the data were consistent with transfer.

But whatever the origin of the tau, Dr. Diamond said he is skeptical that tau is playing a large role in either PD or HD, noting that the level of pathology in either disease is not high. “That said, there is coincidence of tau pathology with alpha-synuclein pathology in a lot of Alzheimer's disease cases, and so it is conceivable that therapies are going to have to target both proteins to be effective.”

The evidence presented in this study supporting the hypothesis that tau spreads in a prion-like way into grafted tissue is intriguing, said Lary C. Walker, PhD, associate professor of neurology at Emory University School of Medicine and research professor at the Yerkes National Primate Research Center in Atlanta.

“But tauopathy occurs in more than 20 different diseases, and it is important to recognize that it can be a non-specific response to stress and may not have anything to do with a specific disease mechanism,” he said. Like other proteins implicated in neurodegenerative disease, including alpha-synuclein and huntingtin, tau's structure lends itself to misfolding and aggregation.

Whether the tau pathology seen here and in other studies of HD and PD contributes to the clinical picture is still an open question, Dr. Walker said. It may be that the level observed in these patients is mild enough to have few functional consequences; more studies would be needed to answer this definitively.

As for fetal transplants, the lessons from this and previous studies showing the spread of pathology are mixed. On the one hand, Dr. Walker said, grafting healthy tissue into a diseased brain appears to be “like trying to rebuild a burning building while it's still on fire. Eventually the graft will get sick. But having said that, if you can get a number of years of better quality of life from a functional graft,” as seems to be the case in at least some PD patients, “it may still be beneficial.”

EXPERTS: ON PRION-LIKE TAU PATHOLOGY IN HD AND PD

FU2-11

DR. MARK DIAMOND said he is skeptical that tau is playing a large role in either PD or HD, noting that the level of pathology in either disease is not high. “That said, there is a coincidence of tau pathology with alpha-synuclein pathology in a lot of Alzheimer's disease cases, and so it is conceivable that therapies are going to have to target both proteins to be effective.”

FU3-11

DR. LARY C. WALKER said whether the tau pathology seen here and in other studies of HD and PD contributes to the clinical picture is still an open question, and more studies would be needed to answer this definitively.

LINK UP FOR MORE INFORMATION:

• Cisbani G, Maxan A, Kordower JH, Planel E, Freeman TB, Cicchetti F. Presence of tau pathology within foetal neural allografts in patients with Huntington's and Parkinson's disease https://academic.oup.com/brain/article-abstract/140/11/2982/4563645. Brain 2017;140(11):2982–2992.