Fetal Cells Function in Parkinson's Brains Years Later

Ricki Lewis, PhD

June 06, 2014

Evaluating the efficacy of fetal grafts to treat Parkinson's disease (PD) takes many years, confirming earlier findings that the cells retain activity and normal morphology up to 14 years later.

Penelope J. Hallett, PhD, from the Neuroregeneration Research Institute, Harvard University, Boston, and McLean Hospital, Belmont, Massachusetts, and colleagues at Dalhousie University, Halifax, Nova Scotia, Canada, evaluated dopamine transporter (DAT) function and a mitochondrial marker in 5 postmortem brains.

These data "support clinical and neuroimaging findings of the long-lasting functional benefit of dopamine neuron transplantation in PD patients."

The study was published online June 5 in Cell Reports.

Ups and Downs

Fetal cell transplantation to treat PD has had its ups and downs. Initial promising results in the early 1990s led to "disappointing" findings a decade later.

Yet in early 2010, a Scientific American headline declared "Fetal Cells Return as a Parkinson's Cure." Some patients are still improving 18 years after transplant.

The fetal cells, delivered as a suspension, must coexist with the host's brain neurons. Rarely, transplanted cells develop Lewy body–like inclusions, presumably from toxic proteins secreted by neighboring neurons that remain in the grip of continuing pathology.

The researchers cite studies that indicate downregulation of DATs in transplanted neurons and that suggest the disease has affected these cells. These reports were an impetus to look further for evidence of efficacy.

The new study builds on the group's evaluation of 5 postmortem brains from patients who underwent transplantation 4 to 14 years earlier. The patients improved, with no adverse effects or histopathology.

The current study assesses DAT expression and the mitochondrial marker Tom20, which is a translocase in the outer mitochondrial membrane. Abnormalities in mitochondrial function reflect aging.

Results were encouraging. Immunofluorescence staining for DAT in dopaminergic neurons and fibers indicated healthy-appearing transplanted cells. Two patients had fetal cells near as well as farther away from the graft. Punctate staining was consistent with synaptic localization.

For 1 brain, the investigators compared DAT staining on the treated side with the untreated side. They found low levels in the untransplanted striatum but persistence of DAT expression in the grafted areas.

Staining for Tom20 was robust in the perikarya and processes of transplanted neurons, as it is in healthy neurons. However, in the patients' substantia nigra cells also stained for α-synuclein, Tom20 appeared in the soma and around the nucleus but not in axons or dendrites. Neurons in the graft region costained for Tom20 and α-synuclein showed normal distribution of the mitochondrial marker and no Lewy bodies.

The study demonstrates long-term graft survival, with DAT localized in axons in the reinnervated striatum, and no mitochondrial abnormalities. These results are "consistent with clinical and neuroimaging data showing stable dopamine cell survival and function" years after surgery, the researchers conclude.

They hypothesize that previous studies identified possible downregulated dopamine synthesis because they focused on the soma, not fibers reinnervating the putamen.

The investigators suggest that instead of misfolded protens spreading from pathologic neurons to healthy graft neurons, perhaps the transplanted cells help to clear unfolded proteins.

The researchers have disclosed no relevant financial relationships.

Cell Rep. Published online June 5, 2014. Abstract

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