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Contains fulltext : 175952.pdf (publisher's version ) (Open Access), Parkinson's disease is caused by a complex interplay of genetic and environmental factors. Although a number of independent molecular pathways and processes have been associated with familial Parkinson's disease, a common mechanism underlying especially sporadic Parkinson's disease is still largely unknown. In order to gain further insight into the etiology of Parkinson's disease, we here conducted genetic network and literature analyses to integrate the top-ranked findings from thirteen published genome-wide association studies of Parkinson's disease (involving 13.094 cases and 47.148 controls) and other genes implicated in (familial) Parkinson's disease, into a molecular interaction landscape. The molecular Parkinson's disease landscape harbors four main biological processes-oxidative stress response, endosomal-lysosomal functioning, endoplasmic reticulum stress response, and immune response activation-that interact with each other and regulate dopaminergic neuron function and death, the pathological hallmark of Parkinson's disease. Interestingly, lipids and lipoproteins are functionally involved in and influenced by all these processes, and affect dopaminergic neuron-specific signaling cascades. Furthermore, we validate the Parkinson's disease -lipid relationship by genome-wide association studies data-based polygenic risk score analyses that indicate a shared genetic risk between lipid/lipoprotein traits and Parkinson's disease. Taken together, our findings provide novel insights into the molecular pathways underlying the etiology of (sporadic) Parkinson's disease and highlight a key role for lipids and lipoproteins in Parkinson's disease pathogenesis, providing important clues for the development of disease-modifying treatments of Parkinson's disease.

The correct identity and functional capacity of transplanted dopamine (DA) neurons derived in vitro from embryonic stem (ES) cells is a critical factor for the development of an ES cell-based replacement therapy for Parkinson's disease. We transplanted primate Cyno-1 ES cells differentiated in vitro for 4 (progenitor ES cells) or 6 (differentiated ES cells) weeks, or control fetal primate cells into the striatum of hemi-parkinsonian rats. Partial behavioral recovery in amphetamine-induced rotation was correlated with the number of ES-derived tyrosine hydroxylase-positive (TH +) neurons in the grafts (r = 0.5, P < 0.05). Post mortem analysis of ES-derived grafts revealed TH + neurons with mature morphology, similar to fetal DA neurons, and expression of midbrain transcription factors, such as Engrailed (En) and Nurr-1. While the total number of TH + neurons was not different between the two groups, TH/En co-expression was significantly higher (> 90%) in grafts from differentiated ES cells than in grafts derived from progenitor cells (< 50%), reflecting a more heterogeneous cellular composition. Within the grafts there was an overlap between ES-derived TH + axonal arbors and clusters of primate ES-derived striatal neurons expressing brain factor 1 (Bf-1, Foxg1) and DA and cAMP-regulated phosphoprotein (DARPP-32). Such overlap was never observed for other regional transcription factors that define neighboring forebrain domains in the developing brain, such as Nkx2.1 (medial ganglionic eminence), Nkx2.2 (pallidal and diencephalic progenitors) or Pax6 (dorsal telencephalic progenitors). Despite the heterogeneity of ES-derived graft cell composition, these results demonstrate normal phenotypic specification, conserved natural axonal target selectivity and functionality of DA neurons derived from primate ES cells. © The Authors (2006).

Dopamine (DA) neurons can be derived from human and primate embryonic stem (ES) cells in vitro. An ES cell-based replacement therapy for patients with Parkinson's disease requires that in vitro-generated neurons maintain their phenotype in vivo. Other critical issues relate to their proliferative capacity and risk of tumor formation, and the capability of migration and integration in the adult mammalian brain. Neural induction was achieved by coculture of primate parthenogenetic ES cells (Cyno-1) with stromal cells, followed by sequential exposure to midbrain patterning and differentiation factors to favor DA phenotypic specification. Differentiated ES cells were treated with mitomycin C and transplanted into adult immunosuppressed rodents and into a primate (allograft) without immunosuppression. A small percentageof DA neurons survived in both rodent and primate hosts for the entire term of the study (4 and 7 months, respectively). Other neuronal and glial populations derived from Cyno-1 ES cells showed, in vivo, phenotypic characteristics and growth and migration patterns similar to fetal primate transplants, and a majority of cells (>80%) expressed the forebrain transcription factor brain factor 1. No teratoma formation was observed. In this study, we demonstrate long-term survival of DA neurons obtained in vitro from primate ES cells. Optimization of differentiation, cell selection, and cell transfer is required for functional studies of ES-derived DA neurons for future therapeutic applications. ©AlphaMed Press.