Lewy Bodies' absence in grafted dopaminergic transplants in Parkinson's Disease

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Authors:  Diana Angelika Olszewska and Tim Lynch

Article first published online:   19 AUG 2015 | DOI: 10.1002/mdc3.12180

Hallett PJ, Cooper O, Sadi D, et al. Long-term health of dopaminergic neuron transplants in Parkinson's disease patients. Cell Rep2014;7:1755–1761.

Parkinson's disease remains an incurable, challenging condition with only symptomatic treatment available. Loss of dopaminergic neurons in the SNc is characteristic and symptoms develop once 60% to 80% of the neurons are lost.[2]

The concept of human, embryonic dopamine neuron transplantation into striatum and SN for treatment of PD has been under investigated since the 1980s.[3, 4] However, results have varied and the role of immunosuppression remains controversial. Grafts may be transplanted either as a solid ventral midbrain piece or a cell suspension.[4] Trials involving sham surgery with solid grafts without use of immunosuppression (Freed 2001)[4] or with low-dose cyclosporine for 6 months. (Olanow 2003)[5] showed motor-symptoms improvement post-transplantation for up to 6 to 9 months only. The lack of benefit beyond 9 months might be explained by the fact that solid grafts are probably more immunogenic.[4] Interestingly, patients from Lund, where cell suspension and triple regimen of cyclosporine, prednisolone, and azathioprine were used for 1 year, showed motor improvement over 18 months.[4]

Aside from the immunosuppression controversy, there is significant concern about potential spread of toxic proteins from native to transplanted neurons seeding these cells and resulting in Lewy body (LB) cell-to-cell spread. Isolated LB-like inclusions staining for alpha-synuclein and ubiquitin and with reduced immunolabeling for dopamine transporter (DAT) were observed in grafts 16 years post-transplantation. However, this is unlikely to influence the overall graft performance given that it occurs in 1% to 5% of neurons only and was observed in only 3 of 20 postmortem case series.[2, 6, 7] Interestingly, clinical benefit may begin 1 year post-transplantation and continue for up to 18 years, as described by Kefalopoulou et al.[8] suggesting that any potential motor improvement settle with time.[8]

Recently Hallett et al.[9] in a follow-up study to Mendez et al.[7, 8] and Cooper et al.,[7] examined long-term health and survival of fetal dopaminergic neuron grafts in postmortem studies of 5 patients by assessing DAT expression and mitochondrial health using the mitochondrial marker, Tom 20 antibody (translocase of outer mitochondrial membrane 20 homolog). Two of the patients had unilateral grafts transplanted (subject 2: right striatum and right midbrain; subject 5: left putamen), whereas the remaining 3 had bilateral transplantation to the right and left putamen.[10, 11] Graft DAT expression was maintained at 14 years, confirmed both by immunofluorescence staining using a monoclonal antibody and a dopamine neuron phenotypic marker (tyrosine hydroxylase). The “control” nontransplanted side in subject 2 showed the expected severe loss of DAT expression in a nontransplanted putamen.

Immunoreactivity in the graft and neighboring regions was not detected. Tom 20 antibody staining in a 4-year-old graft was similar to a healthy brain, but less intense at 9 and 14 years. There was no accumulation of damaged mitochondria, and LBs were absent in grafted tissue, in contrast to findings in the host tissue.

Hallet et al.'s[9] report contradicts the belief that fetal cell grafts undergo significant neurodegeneration and support the clinical evidence of long-term benefit of dopaminergic transplants. This observation is of paramount value for future neuronal transplant therapies in PD.


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