Showing papers by "Anders Björklund published in 2012"

Impaired neurotransmission caused by overexpression of α-synuclein in nigral dopamine neurons

Abstract: We used in vivo amperometry to monitor changes in synaptic dopamine (DA) release in the striatum induced by overexpression of human wild-type α-synuclein in nigral DA neurons, induced by injection of an adeno-associated virus type 6 (AAV6)–α-synuclein vector unilaterally into the substantia nigra in adult rats. Impairments in DA release evolved in parallel with the development of degenerative changes in the nigrostriatal axons and terminals. The earliest change, seen 10 d after vector injection, was a marked, ≈50%, reduction in DA reuptake, consistent with an early dysfunction of the DA transporter that developed before any overt signs of axonal damage. At 3 wk, when the first signs of axonal damage were observed, the amount of DA released after a KCl pulse was reduced by 70–80%, and peak DA concentration was delayed, indicating an impaired release mechanism. At later time points, 8–16 wk, overall striatal innervation density was reduced by 60–80% and accompanied by abundant signs of axonal damage in the form of α-synuclein aggregates, axonal swellings, and dystrophic axonal profiles. At this stage DA release and reuptake were profoundly reduced, by 80–90%. The early changes in synaptic DA release induced by overexpression of human α-synuclein support the idea that early predegenerative changes in the handling of DA may initiate, and drive, a progressive degenerative process that hits the axons and terminals first. Synaptic dysfunction and axonopathy would thus be the hallmark of presymptomatic and early-stage Parkinson disease, followed by neuronal degeneration and cell loss, characteristic of more advanced stages of the disease.

Alpha-Synuclein Cell-to-Cell Transfer and Seeding in Grafted Dopaminergic Neurons In Vivo

Abstract: Several people with Parkinson's disease have been treated with intrastriatal grafts of fetal dopaminergic neurons. Following autopsy, 10-22 years after surgery, some of the grafted neurons contained Lewy bodies similar to those observed in the host brain. Numerous studies have attempted to explain these findings in cell and animal models. In cell culture, α-synuclein has been found to transfer from one cell to another, via mechanisms that include exosomal transport and endocytosis, and in certain cases seed aggregation in the recipient cell. In animal models, transfer of α-synuclein from host brain cells to grafted neurons has been shown, but the reported frequency of the event has been relatively low and little is known about the underlying mechanisms as well as the fate of the transferred α-synuclein. We now demonstrate frequent transfer of α-synuclein from a rat brain engineered to overexpress human α-synuclein to grafted dopaminergic neurons. Further, we show that this model can be used to explore mechanisms underlying cell-to-cell transfer of α-synuclein. Thus, we present evidence both for the involvement of endocytosis in α-synuclein uptake in vivo, and for seeding of aggregation of endogenous α-synuclein in the recipient neuron by the transferred α-synuclein. Finally, we show that, at least in a subset of the studied cells, the transmitted α-synuclein is sensitive to proteinase K. Our new model system could be used to test compounds that inhibit cell-to-cell transfer of α-synuclein and therefore might retard progression of Parkinson neuropathology.

α-Synuclein–Induced Down-Regulation of Nurr1 Disrupts GDNF Signaling in Nigral Dopamine Neurons

Abstract: Glial cell line-derived neurotrophic factor (GDNF) and its close relative neurturin are currently in clinical trials for neuroprotection in patients with Parkinson disease (PD). However, in animal models of PD, GDNF fails to protect nigral dopamine (DA) neurons against α-synuclein-induced neurodegeneration. Using viral vector delivery of human wild-type α-synuclein to nigral DA neurons in rats, we show that the intracellular response to GDNF is blocked in DA neurons that overexpress α-synuclein. This block is accompanied by reduced expression of the transcription factor Nurr1 and its downstream target, the GDNF receptor Ret. We found that Ret expression was also reduced in nigral DA neurons in PD patients. Conditional knockout of Nurr1 in mice resulted in reduced Ret expression and blockade of the response to GDNF, whereas overexpression of Nurr1 restored signaling, providing protection of nigral DA neurons against α-synuclein toxicity. These results suggest that Nurr1 is a regulator of neurotrophic factor signaling and a key player in the cellular defense against α-synuclein toxicity.

Equality of opportunity and the distribution of long-run income in Sweden

Abstract: Equality of opportunity is an ethical goal with almost universal appeal. The interpretation taken here is that a society has achieved equality of opportunity if it is the case that what individuals ...

Serotonin Neuron Loss and Nonmotor Symptoms Continue in Parkinson’s Patients Treated with Dopamine Grafts

Abstract: Cell therapy studies in patients with Parkinson's disease (PD) have been confined to intrastriatal transplantation of dopamine-rich fetal mesencephalic tissue in efforts to improve motor performance. Although some PD patients receiving the dopamine-rich grafts showed improvements in motor symptoms due to replacement of dopaminergic neurons, they still suffered from nonmotor symptoms including depression, fatigue, visual hallucinations, and sleep problems. Using functional imaging and clinical evaluation of motor and nonmotor symptoms in three PD patients transplanted with intrastriatal fetal grafts 13 to 16 years previously, we assessed whether reestablishment of dopaminergic neuronal networks is sufficient to improve a broad range of symptoms. At 13 to 16 years after transplantation, dopaminergic innervation was restored to normal levels in basal ganglia and preserved in a number of extrabasal ganglia areas. These changes were associated with long-lasting relief of motor symptoms. Then, we assessed the integrity of their serotonergic and norepinephrine neuronal systems using [¹¹C]DASB {[¹¹C]3-amino-4-(2-dimethylaminomethylphenylthio) benzonitrile} positron emission tomography (PET) and ¹⁸F-dopa PET, respectively. ¹⁸F-dopa uptake in the locus coeruleus was within the normal range. In contrast, [¹¹C]DASB uptake in the raphe nuclei and regions receiving serotonergic projections was markedly reduced. These results indicate ongoing degeneration of serotonergic raphe nuclei and their projections to regions involved in the regulation of sleep, arousal, feeding, satiety, mood, and emotion. Our findings indicate that future cell-based therapies using fetal tissue or stem cells in PD patients may require additional grafts of serotonergic neurons to relieve nonmotor symptoms by restoring serotonergic neurotransmission in specific cerebral targets.

Survival, differentiation, and connectivity of ventral mesencephalic dopamine neurons following transplantation

Abstract: The reconstruction of midbrain dopamine (DA) circuitry through intracerebral transplantation of new DA neurons contained in embryonic ventral mesencephalon (VM) is a promising therapeutic approach for Parkinson's disease (PD) Although some of the early open-label trials have provided proof-of-principal that VM grafts can provide sustained improvement of motor function in some patients, subsequent trials showed that the functional response can be highly variable This chapter reviews an extensive body of basic and clinical research on the survival, differentiation, and connectivity of DA neurons in VM grafts, and also looks at how these parameters are affected by certain host- and donor-specific variables We also review how technical advances in the tools available to study the integration of grafted DA neurons, such as transgenic reporter mice, have made significant contributions to our understanding of the capacity of different DA neuronal subtypes for target-directed growth and innervation of appropriate host brain structures Our established and on-going understanding of the capacity of grafted DA neurons to structurally and functionally integrate following transplantation forms an important basis for the refinement and optimization of VM grafting procedures, and also the development of new procedures based on the use of stem cells

Introduction (Part I)

Abstract: Functional neural transplantation has come a long way in the past four decades Pioneering studies during the1970s and early1980s established basic methods for achieving effective survival and integration of embryonic neuronal tissue grafts in the mammalian central nervous system so that, in the early 1980s, three major review volumes covering this new field appeared in close succession (Bjorklund and Stenevi, 1985; Sladek and Gash, 1984; Wallace and Das, 1983) Their focus was largely on the principles of defining the technical aspects of delivery, demonstrating neuronal survival, characterizing anatomical growth of connections between grafted cells and the host brain, and providing the first biochemical, physiological, and simple assessments of function From the outset, there was an interest in whether functional recovery in simple animal models might presage the way to eventual clinical applications of novel surgical strategies to treat hitherto untreatable neurological diseases By the early 1990s, the capacity of neural transplants to alleviate functional deficits in animal models of a range of neurodegenerative conditions was well established, and the feasibility of translation dramatically established by the first demonstration of unequivocal functional benefit in Parkinson’s disease, at least for some patients (Lindvall et al, 1990) This led us to coordinate the first major review volume, Functional Neural Transplantation, focusing explicitly on the range of animal models that were then being used to evaluate the functional efficacy of neural grafts, exploring the mechanisms and conditions for functional recovery, and summarizing the first clinical applications, most notably in Parkinson’s disease, but also looking forward to applications in a range of other conditions, including Huntington’s disease, aging, ischemia, spinal cord injury, and metabolic disease (Dunnett and Bjorklund, 1994) By the time of the second review volume, Functional Neural Transplantation II, 8 years later, alternative sources of cells were now being considered, including immortalized cell lines, cell encapsulation, and xenotransplantation (Dunnett and Bjorklund, 2000); although the first human embryonic stem cell lines were clearly appearing on the horizon, they had not yet translated to functional transplantation even in animal models Clinical studies had by now commenced in several other

The Role of Parental Income Over the Life Cycle: A Comparison of Sweden and the UK

Abstract: Research on intergenerational income mobility has shown stronger persistence between parental and offspring's income in the UK than in Sweden. We use similar data sets for the two countries to explore whether these cross-national differences show up already early in offspring's life in outcomes such as birth weight, grades at the end of compulsory school at age 16, height during adolescence, and final educational attainment. We do indeed find significant country differences in the association between parental income and these outcomes, and the associations are stronger in the UK than in Sweden.Therefore, we continue to investigate whether these differentials are large enough to account for a substantial part of the difference in intergenerational persistence estimates. We then conclude that the country differences in the intergenerational associations in birth weight and height are too weak to account for hardly any fraction of the UK-Sweden difference in intergenerational income mobility. For the more traditional human-capital variables grades and final education, however, our results suggest that the country differences can account for a substantial part of the difference in income persistence.

The role of parental income over the life cycle: A comparison of Sweden and the UK

Abstract: Research on intergenerational income mobility has shown stronger persistence between parental and offspring's income in the UK than in Sweden. We use similar data sets for the two countries to explore whether these cross-national differences show up already early in offspring's life in outcomes such as birth weight, grades at the end of compulsory school at age 16, height during adolescence, and final educational attainment. We do indeed find significant country differences in the association between parental income and these outcomes, and the associations are stronger in the UK than in Sweden. Therefore, we continue to investigate whether these differentials are large enough to account for a substantial part of the difference in intergenerational persistence estimates. We then conclude that the country differences in the intergenerational associations in birth weight and height are too weak to account for hardly any fraction of the UK-Sweden difference in intergenerational income mobility. For the more traditional human-capital variables grades and final education, however, our results suggest that the country differences can account for a substantial part of the difference in income persistence.