Parkinson Disease: Vinuela A

Astradsson A, Cooper O, Vinuela A, Isacson O. · NINDS Udall Parkinson's Disease Research Center of Excellence, Harvard University and McLean Hospital, Belmont, Massachusetts 02478, USA. · Neurosurg Focus. · Pubmed #18341409 No free full text.

Abstract: In this review, the authors discuss recent advances in the field of cell therapy for Parkinson disease (PD). They compare and contrast recent clinical trials using fetal dopaminergic neurons. They attribute differences in cell preparation techniques, cell type specification, and immunosuppression as reasons for variable outcome and for some of the side effects observed in these clinical trials. To address ethical, practical, and technical issues related to the use of fetal cell sources, alternative sources of therapeutic dopaminergic neurons are being developed. The authors describe the progress in enrichment and purification strategies of stem cell-derived dopaminergic midbrain neurons. They conclude that recent advances in cell therapy for PD will create a viable long-term treatment option for synaptic repair for this debilitating disease.

Vinuela A, Hallett PJ, Reske-Nielsen C, Patterson M, Sotnikova TD, Caron MG, Gainetdinov RR, Isacson O. · Udall Parkinson Disease Research Center of Excellence,Center for Neuroregeneration Research, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA. · Brain. · Pubmed #18988638 links to  free full text

Abstract: OFF-L-dopa dyskinesias have been a surprising side-effect of intrastriatal foetal ventral mesencephalic transplantation in patients with Parkinson's disease. It has been proposed that excessive and unregulated dopaminergic stimulation of host post-synaptic striatal neurons by the grafts could be responsible for these dyskinesias. To address this issue we transplanted foetal dopaminergic neurons from mice lacking the dopamine transporter (DATKO) or from wild-type mice, into a rat model of Parkinson's disease and L-dopa-induced dyskinesias. Both wild-type and DATKO grafts reinnervated the host striatum to a similar extent, but DATKO grafts produced a greater and more diffuse increase in extra-cellular striatal dopamine levels. Interestingly, grafts containing wild-type dopaminergic neurons improved parkinsonian signs to a similar extent as DATKO grafts, but provided a more complete reduction of L-dopa induced dyskinesias. Neither DATKO nor wild-type grafts induced OFF-L-dopa dyskinesias. Behavioural and receptor autoradiography analyses demonstrated that DATKO grafts induced a greater normalization of striatal dopaminergic receptor supersensitivity than wild-type grafts. Both graft types induced a similar downregulation and normalization of PEnk and fosb/Deltafosb in striatal neurons. In summary, DATKO grafts causing high and diffuse extra-cellular dompamine levels do not per se alter graft-induced recovery or produce OFF-L-dopa dyskinesias. Wild-type dopaminergic neurons appear to be the most effective neuronal type to restore function and reduce L-dopa-induced dyskinesias.

de Chevigny A, Cooper O, Vinuela A, Reske-Nielsen C, Lagace DC, Eisch AJ, Isacson O. · Udall Parkinson Disease Research Center of Excellence, Center for Neuroregeneration Research, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA. · Stem Cells. · Pubmed #18556510 No free full text.

Abstract: Infusion of transforming growth factor alpha (TGFalpha) into the adult dopamine (DA)-depleted striatum generates a local population of nestin(+)/proliferating cell nuclear antigen (PCNA)(+) newborn cells. The precise origin and fate of these new striatal cells are unknown, making it difficult to direct them for neural repair in Parkinson's disease. Experiments in rats using 5-bromo-2'-deoxyuridine (BrdU) to label neural progenitor cells showed that during TGFalpha infusion in the DA-depleted striatum, newborn striatal cells formed a homogeneous population of precursors, with the majority coexpressing nestin, Mash1, Olig2, and epidermal growth factor receptor, consistent with the phenotype of multipotent C cells. Upon TGFalpha pump withdrawal, the subventricular zone (SVZ) was repopulated by neuroblasts. Strikingly, during this period, numerous clusters of doublecortin(+)/polysialylated neuronal cell adhesion molecule(+) neuroblasts were also produced in the ipsilateral medial striatum. In parallel, striatal BrdU(+)/glial fibrillary acidic protein(+) astrocytes were generated, but no BrdU(+)/O4(+)/CNPase(+) oligodendrocytes were generated. Infusion of the neuralizing bone morphogenetic protein antagonist noggin after TGFalpha pump withdrawal increased the neuroblast-to-astrocyte ratio among new striatal cells by blocking glial differentiation but did not alter striatal neurogenesis. At no time or treatment condition were differentiated neurons generated, including DA neurons. Using 6-hydroxydopamine-lesioned nestin-CreER(T2)/R26R-YFP mice that allow genetic fate-mapping of SVZ nestin(+) cells, we show that TGFalpha-generated striatal cells originate from SVZ nestin(+) precursors that confirmed data from the rats on the phenotype and fate of striatal nestin(+)/PCNA(+) cells upon TGFalpha withdrawal. This work demonstrates that a large population of multipotent striatal C-like cells can be generated in the DA-depleted striatum that do not spontaneously differentiate into DA neurons.