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Wernig M, Zhao JP, Pruszak J, Hedlund E, Fu D, Soldner F, Broccoli V, Constantine-Paton M, Isacson O, Jaenisch R. Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson's disease. Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5856-61. PubMed.
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Harvard Medical School
I think the impression created by the Li and Kordower papers that there is “PD pathology in the transplants ” is unfortunate. The papers give the impression of an “either/or” proposition of "pathology" in the transplant cases, but neither paper provides a clear description of proportion (such as percent) of neurons with “Lewy bodies.”
The facts are that in the material of Kordower et al., the vast majority of dopamine neurons in each transplant case (containing many thousands of new dopamine neurons) do not have any α-synuclein aggregates, which I have personally studied with primary data and the same staining used in Mendez et al., as stated in this news article by Tom Fagan. We estimate that less than 1 percent of dopamine neurons in the one Kordower et al. case have any protein inclusions. Moreover, as Dr. Trojanowski points out, we do not know if such α-synuclein inclusions are necessarily permanent and direct evidence of PD, or simply a low-level dynamic shift in protein distribution and aggregation that may also occur in the normal brain.
Even more misleading are the percentages of α-synuclein stained neurons in the Li et al. paper. Fagan correctly cites this on Alzforum: “In the patient with 12- and 16-year-old grafts, about 40 percent of TH-positive neurons contained detectable α-synuclein in the youngest graft, while about 80 percent of the cells were α-synuclein-positive in the older graft.” Here the misleading notion is born (as evidently misunderstood by every commentary on these papers so far) that such staining represents Lewy body pathology. Instead, the vast majority of neurons in the Li et al. case (as in the Kordower et al. case) are not staining for α-synclein inclusions. In the Li et al. case, too, this is not fully quantified. The authors simply show α-synclein protein staining, which is expected and normal, as Dr. Trojanowski points out. α-synuclein is a normal protein with both cellular and synaptic distribution and function.
In summary, so far all of our cases and Dr. Freed’s seven cases up to 14 years after surgery have no signs of α-synuclein pathology. In transplants surviving for up to 16 years, the papers by Li et al. and Kordower et al. demonstrate that a small fraction of neurons contain α-synuclein stained inclusions. From these data, one cannot conclude that there is a PD process transferred from the patient to the transplant, or that PD is simply caused by a non-cell-autonomous process.
From a potentially important future treatment perspective, all the evidence actually shows that it is reasonable to assume that similar dopamine neurons obtained from other cell sources in the future, for example, stem cells, could survive without pathology and function for at least 15 years without significant problems generated by the PD of the host.
View all comments by Ole IsacsonUniversity of California, San Diego
These studies elegantly demonstrate that transplanted fetal grafts can survive and thrive in human brains for prolonged periods, clearly moving the field in new, exciting directions. However, the view that the presence of α-synuclein in these grafted neurons represents a “host to graft” disease progression needs further scrutiny.
Though it may seem parsimonious to assume that the accumulation of α-synuclein in these grafts is due to the environment in which the grafts are, a closer inspection of the facts argue that the “accumulation” of α-synuclein seen in these grafted neurons may be related to the biology of the protein.
First, as pointed out previously, it has been shown that α-synuclein is present in the perikarya of fetal neurons (Galvin et al., 2001; Raghavan et al., 2004), and that over time, the protein is predominantly localized to presynaptic boutons/terminals. This is especially apparent in a reduced system like cultured hippocampal neurons, where the protein is initially abundant in the perikarya, and over time, as synapses develop, most of the protein is concentrated at the boutons (Withers et al., 1997;Roy et al., 2007). Indeed, this behavior is not unique for α-synuclein, as most presynaptic proteins tend to behave similarly in human brains (Galvin et al., 2001) as well as in cultured neurons (Fletcher et al., 1991). Thus, the perikaryal α-synuclein accumulation may simply be a manifestation of the immature state of these neurons.
One prediction of this model would be that other presynaptic proteins would also show a similar perikaryal distribution. Though it can be argued that the time-course of the grafted neurons should allow the fetal neurons to mature enough so that their presynaptic proteins can be redistributed from the perikarya to synapses, the onus is upon the authors to show that this indeed is the case.
A second point worth considering is that α-synuclein does not spontaneously appear at the presynapses, but is continuously synthesized at the perikarya and then transported along the axon up to the synapses (Jensen et al., 1999; Li et al., 2004; Roy et al., 2007) throughout the life of the neuron, much like any other synaptic or non-synaptic protein including ubiquitin. As the grafted neurons in these studies seem to grow with no apparent organization, it is conceivable that this atypical organization of grafted neurons is not conducive to physiologic axonal transport in these neurons, causing proteins (including α-synuclein) to accumulate in cell bodies and axons. Both these scenarios seem reasonable, and can perhaps more easily explain the phenotype, as opposed to the alternative but more exotic proposal of disease-induction in the grafted neurons.
In summary, I would definitely recommend these papers, but would argue that we must apply critical judgment in our interpretation of the α-synuclein story.
References:
Fletcher TL, Cameron P, De Camilli P, Banker G. The distribution of synapsin I and synaptophysin in hippocampal neurons developing in culture. J Neurosci. 1991 Jun;11(6):1617-26. PubMed.
Galvin JE, Schuck TM, Lee VM, Trojanowski JQ. Differential expression and distribution of alpha-, beta-, and gamma-synuclein in the developing human substantia nigra. Exp Neurol. 2001 Apr;168(2):347-55. PubMed.
Jensen PH, Li JY, Dahlström A, Dotti CG. Axonal transport of synucleins is mediated by all rate components. Eur J Neurosci. 1999 Oct;11(10):3369-76. PubMed.
Li W, Hoffman PN, Stirling W, Price DL, Lee MK. Axonal transport of human alpha-synuclein slows with aging but is not affected by familial Parkinson's disease-linked mutations. J Neurochem. 2004 Jan;88(2):401-10. PubMed.
Raghavan R, Kruijff L, Sterrenburg MD, Rogers BB, Hladik CL, White CL. Alpha-synuclein expression in the developing human brain. Pediatr Dev Pathol. 2004 Sep-Oct;7(5):506-16. PubMed.
Roy S, Winton MJ, Black MM, Trojanowski JQ, Lee VM. Rapid and intermittent cotransport of slow component-b proteins. J Neurosci. 2007 Mar 21;27(12):3131-8. PubMed.
Withers GS, George JM, Banker GA, Clayton DF. Delayed localization of synelfin (synuclein, NACP) to presynaptic terminals in cultured rat hippocampal neurons. Brain Res Dev Brain Res. 1997 Mar 17;99(1):87-94. PubMed.
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