Misfolded proteins in Huntington disease fetal grafts: Further evidence of cell‐to‐cell transfer?

In an article published in this issue of Annals of Neurology, Cicchetti and coworkers report the presence of mutant huntingtin (mHtt) within fetal striatal grafts placed within the putamen of patients with Huntington disease (HD) approximately 10 years prior. All of the grafts were derived from normal donors, and there was no possibility that these grafted tissues were from HD donors who ultimately would have developed such a pathology. These cases were evaluated and reported previously but HD pathology in the graft neuropil was not observed in these previous publications (in 1 of which J.H.K. was a coauthor). However, using newer, more sensitive techniques, mHtt was seen in the present article using multiple antibodies, and the presence of these extracellular inclusions within the graft borders appears clear. On the surface, this finding could be the most unambiguous demonstration of protein transmission between cells in the brains of humans receiving fetal transplants. We and others have demonstrated the presence of intracellular Lewy bodies within transplanted fetal nigral neurons in patients with Parkinson disease (PD). These cases, along with preclinical studies, support the emerging concept of cell-to-cell transport/transmission of alpha-synuclein pathology in PD and underlie in part the so-called PD prion hypothesis. However, although these are exciting findings, it remains difficult to prove cell-to-cell transmission in human postmortem cases, and the possibility that the Lewy bodies found in the fetal PD grafting cases are the result of cell autonomous pathological processes and not due to cell-to-cell transfer cannot yet be excluded. In the Cicchitti et al article, the findings have the potential to be more definitive, because mHtt should only be found in tissue that carries the mutant huntingtin allele, and it is highly unlikely that it would be found or expressed in tissues derived from donors with normal numbers of CAG repeats. That this misfolded protein occurs in fetal striatal grafts supports the concept that the Lewy bodies found in grafts in PD patients may be due to cell-to-cell transmission. These observations, along with the robust transmission of tau seen in preclinical murine models, support the emerging concept that the transfer of misfolded proteins is a generalized phenomenon in a variety of neurodegenerative diseases. One distinction between the present HD cases and the previously reported PD cases is that the mHtt is found within the grafted neuropil and not in any cellular compartment within neurons, astrocytes, or microglia. This finding contrasts with the Lewy bodies seen in PD grafts, which are found within nigral and non-nigral neurons. The authors postulate a number of theories as to how the mHtt became localized to the neuropil. The one favored by us is that mHtt originates from cortical axons that have extruded this aggregated protein within the graft following degeneration of corticostriatal axons and terminals. The presence of mHtt in the grafted tissue is unlikely to be due to retrograde transport, as one should be able to identify perikarya containing mHtt. In the same vein, it is unlikely that the mHtt was secreted from the host in an anterograde fashion, as fibers containing this misfolded protein should also be found. However, the liberation of the aggregate into the