Showing papers by "Anders Björklund published in 2005"

The Origins of Intergenerational Associations: Lessons from Swedish Adoption Data

Abstract: We use unique Swedish data to estimate intergenerational associations between adoptees and their biological and adoptive parents. We argue that the impact from biological parents captures broad pre-birth factors, including genes and prenatal environment, and the impact from adoptive parents represents broad post-birth factors, such as childhood environment, for the intergenerational association in education and income. We find that both pre- and post-birth factors contribute to intergenerational transmissions, and that pre-birth factors are more important for mother's education and less important for father's income. We also find some evidence for a positive interaction effect between post-birth environment and pre-birth factors.

Factors affecting the clinical outcome after neural transplantation in Parkinson's disease

Abstract: Intrastriatal grafts of embryonic mesencephalic tissue can survive in the brains of patients with Parkinson's disease, but the degree of symptomatic relief is highly variable and some cases develop troublesome dyskinesias. Here we explored, using clinical assessment and 18F-dopa and 11C-raclopride PET, factors which may influence the functional outcome after transplantation. We observed increased 18F-dopa uptake in the grafted putamen, signifying continued survival of the transplanted dopaminergic neurons, in parallel with a progressive reduction of 18F-dopa uptake in non-grafted regions for the whole patient group. The patients with the best functional outcome after transplantation exhibited no dopaminergic denervation in areas outside the grafted areas either preoperatively or at 1 or 2 years post-operatively. In contrast, patients with no or modest clinical benefit showed reduction of 18F-dopa in ventral striatum prior to or following transplantation, which may have limited graft-induced improvement. We obtained no evidence that dyskinesias were caused by abnormal dopamine (DA) release from the grafts. As has been observed for intrinsic dopaminergic neurons, there was a significant correlation between 18F-dopa uptake and methamphetamine-induced change of 11C-raclopride binding (as a measure of DA release) in the putamen containing the graft. Furthermore, we observed no correlation between 11C-raclopride binding in anterior, posterior or entire putamen under basal conditions or after methamphetamine, and dyskinesia severity scores in the contralateral side of the body. Withdrawal of immunosuppression at 29 months after transplantation caused no reduction of 18F-dopa uptake or worsening of UPDRS motor score, indicating continued survival and function of the graft. However, patients showed increased dyskinesia scores, which might have been caused either by growth of the graft or worsening of a low-grade inflammation around the graft. These findings indicate that poor outcome after transplantation is associated with progressive dopaminergic denervation in areas outside the grafts, a process which may have started already before surgery. Also, that the development of dyskinesias after transplantation is not associated with excessive DA release from the grafts. Finally, our data provide evidence that long-term immunosuppression can be withdrawn without interfering with graft survival or the motor recovery induced by transplantation.

Identification of dopaminergic neurons of nigral and ventral tegmental area subtypes in grafts of fetal ventral mesencephalon based on cell morphology, protein expression, and efferent projections.

Abstract: Transplants of fetal ventral mesencephalic tissue are known to contain a mixture of two major dopamine (DA) neuron types: the A9 neurons of the substantia nigra pars compacta (SNpc) and the A10 neurons of the ventral tegmental area (VTA). Previous studies have suggested that these two DA neuron types may differ in their growth characteristics, but, because of technical limitations, it has so far been difficult to identify the two subtypes in fetal ventral mesencephalon (VM) grafts and trace their axonal projections. Here, we have made use of a transgenic mouse expressing green fluorescent protein (GFP) under the tyrosine hydroxylase promoter. The expression of the GFP reporter allowed for visualization of the grafted DA neurons and their axonal projections within the host brain. We show that the SNpc and VTA neuron subtypes in VM grafts can be identified on the basis of their morphology and location within the graft, and their expression of a G-protein-gated inwardly rectifying K+ channel subunit (Girk2) and calbindin, respectively, and also that the axonal projections of the two DA neuron types are markedly different. By retrograde axonal tracing, we show that dopaminergic innervation of the striatum is derived almost exclusively from the Girk2-positive SNpc cells, whereas the calbindin-positive VTA neurons project to the frontal cortex and probably also other forebrain areas. The results suggest the presence of axon guidance and target recognition mechanisms in the DA-denervated forebrain that can guide the growing axons to their appropriate targets and indicate that cell preparations used for cell replacement in Parkinson's disease will be therapeutically useful only if they contain cells capable of generating the correct nigral DA neuron phenotype.

Reversal of dyskinesias in an animal model of Parkinson's disease by continuous L-DOPA delivery using rAAV vectors.

Abstract: Dyskinesias are a major complication of long-term l-3,4-dihydroxyphenylalanine (L-DOPA) treatment in Parkinson's disease, and are believed to result from the intermittent and pulsatile supply of L-DOPA. Daily injections of L-DOPA can prime similar abnormal involuntary movements of the limb, orolingual and axial muscles in rats rendered parkinsonian by destruction of the nigrostriatal dopamine (DA) neurons. In this study we used 33 rats with severe nigrostriatal dopamine depletion and showed that in vivo gene transfer of the DA-synthetic enzymes tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) using recombinant adeno-associated virus vectors can provide a constant source of DOPA production locally in the striatum, at a level that is effective in reducing L-DOPA-induced dyskinesias by >85%, and reverse lesion-induced motor impairments. Furthermore, the abnormal expression of DeltaFosB, prodynorphin and preproenkephalin mRNA within the striatal projection neurons normally seen in dyskinetic animals was completely reversed by TH-GCH1 gene transfer. These findings form a strong basis for replacing, or supplementing, conventional systemic L-DOPA therapy by continuous intrastriatal DOPA using in vivo gene transfer in the treatment of patients with advanced Parkinson's disease.

Isolation and characterization of neural precursor cells from the Sox1-GFP reporter mouse.

Abstract: We have made use of a reporter mouse line in which enhanced green fluorescence protein (GFP) is inserted into the Sox1 locus. We show that the GFP reporter is coexpressed with the Sox1 protein as well as with other known markers for neural stem and progenitor cells, and can be used to identify and isolate these cells by fluorescence-activated cell sorting (FACS) from the developing or adult brain and from neurosphere cultures. All neurosphere-forming cells with the capacity for multipotency and self-renewal reside in the Sox1-GFP-expressing population. Thus, the Sox1-GFP reporter system is highly useful for identification, isolation and characterization of neural stem and progenitor cells, as well as for the validation of alternative means for isolating neural stem and progenitor cells. Further, transplantation experiments show that Sox1-GFP cells isolated from the foetal brain give rise to neurons and glia in vivo, and that many of the neurons display phenotypic characteristics appropriate for the developing brain region from which the Sox1-GFP precursors were derived. On the other hand, Sox1-GFP cells isolated from the adult subventricular zone or expanded neurosphere cultures gave rise almost exclusively to glial cells following transplantation. Thus, not all Sox1-GFP cells possess the same capacity for neuronal differentiation in vivo.

Cell therapy for Parkinson's disease: problems and prospects.

Abstract: Cell replacement therapy in Parkinson's disease (PD) has so far been based on the use of primary dopaminergic (DA) neuroblasts obtained from the brain of aborted human fetuses. Clinical trials show that intrastriatal DA neuron transplants can give substantial symptomatic relief in advanced PD patients. Two recent NIH-sponsored placebo-controlled trials, however, have given disappointing results and highlighted a number of critical issues that need to be resolved in order to turn cell transplantation into an acceptable clinical therapy. First, graft survival and clinical outcome has so far been too variable, suggesting that DA neuron grafts may not be equally effective in all PD patients. Secondly, it has become clear that immune mechanisms leading to slowly developing inflammatory responses may compromise long-term graft survival and function. Third, the problems associated with the use of tissue from aborted fetuses make it necessary to develop alternative sources of cells for transplantation. Recent progress in the generation of DA neuroblasts from neural progenitors and embryonic stem cells suggest that these kinds of cell may offer more accessible, defined and standardized sources of cells for clinical transplantation in PD.

American exceptionalism in a new light : a comparison of intergenerational earnings mobility in the Nordic countries, the United Kingdom and the United States

Abstract: We develop methods and employ similar sample restrictions to analyse differences in intergenerational earnings mobility across the United States, the United Kingdom, Denmark, Finland, Norway and Sweden. We examine earnings mobility among pairs of fathers and sons as well as fathers and daughters using both mobility matrices and regression and correlation coefficients. Our results suggest that all countries exhibit substantial earnings persistence across generations, but with statistically significant differences across countries. Mobility is lower in the U.S. than in the U.K., where it is lower again compared to the Nordic countries. Persistence is greatest in the tails of the distributions and tends to be particularly high in the upper tails: though in the U.S. this is reversed with a particularly high likelihood that sons of the poorest fathers will remain in the lowest earnings quintile. This is a challenge to the popular notion of ’American exceptionalism’. The U.S. also differs from the Nordic countries in its very low likelihood that sons of the highest earners will show downward ’long-distance’ mobility into the lowest earnings quintile. In this, the U.K. is more similar to the U.S.

Functional properties and synaptic integration of genetically labelled dopaminergic neurons in intrastriatal grafts.

Abstract: Intrastriatal grafts of fetal ventral mesencephalic tissue, rich in dopaminergic neurons, can reverse symptoms in Parkinson's disease. For development of effective cell replacement therapy, other sources of dopaminergic neurons, e.g. derived from stem cells, are needed. However, the electrophysiological properties grafted cells need to have in order to induce substantial functional recovery are poorly defined. It has not been possible to prospectively identify and record from dopaminergic neurons in fetal transplants. Here we used transgenic mice expressing green fluorescent protein under control of the rat tyrosine hydroxylase promoter for whole-cell patch-clamp recordings of endogenous and grafted dopaminergic neurons. We transplanted ventral mesencephalic tissue from E12.5 transgenic mice into striatum of neonatal rats with or without lesions of the nigrostriatal dopamine system. The transplanted cells exhibited intrinsic electrophysiological properties typical of substantia nigra dopaminergic neurons, i.e. broad action potentials, inward rectifying currents with characteristic 'sag', and spontaneous action potentials. The grafted dopaminergic neurons also received functional excitatory and inhibitory synaptic inputs from the host brain, as shown by the presence of both spontaneous and stimulation-evoked excitatory and inhibitory postsynaptic currents. Occurrence of spontaneous excitatory and inhibitory currents was lower, and of spontaneous action potentials was higher, in neurons placed in the dopamine-depleted striatum than of those in the intact striatum. Our findings define specific electrophysiological characteristics of transplanted fetal dopaminergic neurons, and we provide the first direct evidence of functional synaptic integration of these neurons into host neural circuitries.

American exceptionalism in a new light: a comparison of intergenerational earnings mobility in the Nordic countries, the United Kingdom and the United States

Abstract: We develop methods and employ similar sample restrictions to analyse differences in intergenerational earnings mobility across the United States, the United Kingdom, Denmark, Finland, Norway and Sweden. We examine earnings mobility among pairs of fathers and sons as well as fathers and daughters using both mobility matrices and regression and correlation coefficients. Our results suggest that all countries exhibit substantial earnings persistence across generations, but with statistically significant differences across countries. Mobility is lower in the U.S. than in the U.K., where it is lower again compared to the Nordic countries. Persistence is greatest in the tails of the distributions and tends to be particularly high in the upper tails: though in the U.S. this is reversed with a particularly high likelihood that sons of the poorest fathers will remain in the lowest earnings quintile. This is a challenge to the popular notion of ’American exceptionalism’. The U.S. also differs from the Nordic countries in its very low likelihood that sons of the highest earners will show downward ’long-distance’ mobility into the lowest earnings quintile. In this, the U.K. is more similar to the U.S..

Histological analysis of fetal dopamine cell suspension grafts in two patients with Parkinson's disease gives promising results

Abstract: In this issue of Brain (pages 1498–1510), Mendez and collaborators report the postmortem analysis of brains from two patients with Parkinson's disease who had received grafts of brain tissue dissected from the developing ventral mesencephalic region, obtained from 6- to 9-week-old aborted fetuses, which is known to contain the appropriate type of dopamine neurones lost in these patients as a result of their disease. The most important aspect of this report is the fact that this is the first time we have been able to evaluate the outcome of so-called cell suspension grafts, a more refined cell preparation technique than has been used in the previously reported autopsy cases. Since 1987, when the first clinical neural transplantation trials were initiated, some 350 Parkinson's disease patients have received intrastriatal grafts of human fetal mesencephalic tissue (Lindvall and Bjorklund, 2004; Winkler et al ., 2005). However, there has so far been no attempt to standardize the way in which the transplantation is carried out at different centres. Almost all aspects of tissue handling and storage, and of graft preparation, have differed from one centre to another (Winkler et al ., 2005). In several open-label trials, such as those performed in Lund, Paris and Halifax, grafts prepared as cell suspensions have been used, whereas other centres …

Parkinson's disease: viral vector delivery of parkin generates model results in rats.

Abstract: In the December 14, 2004 issue of the Proceedings of National Academy of Sciences, Christophe Lo Bianco et al published the first in vivo demonstration of a novel gene therapy for Parkinson’s disease (PD). Using a recombinant lentiviral vector that encoded the parkin gene, the authors were able to block dopamine neurodegeneration in a rat model of PD. PD is characterized by progressive degeneration of the dopamine-producing neurons of the substantia nigra, that is, the pigmented region of the midbrain that gives rise to the nigrostriatal pathway. In most PD cases, which are nonfamilial, the etiology of the disease is unknown, and is thus referred to as idiopathic PD. However, in the last decade, mutations that lead to various inherited forms of the disease have been identified in several genes, two of which have gained particular attention: mutations or duplications in the a-synuclein (a-syn) gene were found to lead to PD in an autosomal dominant manner, and loss of function mutations in a gene named parkin has been found to be associated with an autosomal recessive juvenile form of PD. Interestingly, parkin is one of the several E3 ligases that mediate ubiquitination of mutated or damaged proteins and facilitate the proteosome’s removal of these proteins from the cells. Initial in vitro evidence indicated that a glycosylated (22 kDa) form of a-syn might be a substrate for parkin. According to this model, parkin would ubiquitinate and facilitate degradation of a-syn (left side of Figure 1), and loss-of-function mutations in this gene would thus lead to accumulation of the 22 kDa synuclein protein species. Under this model, the parkin and a-syn mutations that lead to different forms of familial PD converge at the functional level. Conversely, then, enhancement of parkin function should lead to beneficial effects in PD cases. Indeed, transgenic fly models have provided data that indicate that overexpression of parkin could counteract the degenerative changes that the overexpression of a-syn in these models induces. However, the rescue of dopamine neurons in the parkin-a-syn double transgenic flies was seen in the absence of any changes in a-syn protein levels. By contrast, co-expression of parkin and Pael-R – another substrate for parkin – was associated with a profound reduction in detectable Pael-R protein. This difference argues in favor of two different mechanisms of action of parkin. While in the case of Pael-R, the ability of parkin to associate with the proteosomal degradation pathway is the likely explanation for rescue of dopamine neurons, another function of parkin independent of this pathway might protect these neurons from a-synmediated toxicity. Lo Bianco et al show that coexpression of the A30P-mutated form of human a-syn protein and wild-type parkin in the rat brain, using viralvector-mediated gene transfer, leads to protection of the transduced dopamine neurons from a-syn toxicity. Interestingly, however, the number of inclusions, as assessed with an antibody recognizing the a-syn protein phosphorylated at serine residue in position 129 (the form found in pathological Lewy body inclusions in PD patients), was increased rather than decreased in these rats. So, if parkin is not facilitating the degradation of a-synuclein, how does it mediate its protective effects? The authors hypothesize that parkin enhances the sequestration of toxic soluble prefibrillar oligomers into mature hyperphosphorylated inclusions and so promotes dopamine neuron survival (right side in Figure 1). This hypothesis would be in line with the view that the soluble protofibrillar form of a-syn, rather than the aggregated form present in the inclusions, is the toxic species. As the observations reported in the Lo Bianco paper are limited to only 6 weeks survival, it remains unclear if these inclusions could become toxic to a cell over a more protracted time course. This brings up a second question: How would this aggregated a-syn be removed from the cell? Cuervo et al have recently provided evidence that native wild-type a-syn is selectively translocated to lysosomes and normally degraded. It is not known whether the mature hyperphosphorylated inclusions are turning over in the affected cells, and to what extent they might be targeted to the lysosomal compartment for degradation. It is indeed an intriguing question what would happen if the cells were unable to degrade the mutated a-syn. Would the affected dopamine neurons eventually die at a later time, or can the cells function well over a long term in the presence of inclusions that might continuously increase in size and number? Another interesting piece of information comes from another paper by Lo Bianco et al published a few months ago, where they tested the ability of glial cell line-derived neurotrophic factor (GDNF) in the same a-syn overexpression model. Surprisingly, although GDNF has been documented extensively as one of the most potent survivalpromoting factors for DA neurons, it did not have any effect in the a-syn overexpression model. This discrepancy probably highlights the fact that our ability to show efficacy in a given model is dependent on (and is biased towards) the mechanism of action of the toxic insult. Nearly all protective or regenerative effects of GDNF had been shown in neurotoxic lesions that are based on oxidative damage triggered, for example, by inhibition of mitochondrial enzymes. Thus, the present data obtained with overexpression of parkin is highlighting a new pathway to tackle the degenerative process in PD, with actions different from and possibly complementary to GDNF’s neuroprotective effects. This raises the question whether parkin overexpression might be protective also in PD models where mitochondrial toxins induce dopamine neurodegeneration, such as MPTP and rotenone. Indeed, in idioGene Therapy (2005) 12, 727–729 & 2005 Nature Publishing Group All rights reserved 0969-7128/05 $30.00