| 1. |
- Smith, Ruben, et al.
(författare)
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Mutant huntingtin interacts with {beta}-tubulin and disrupts vesicular transport and insulin secretion.
- 2009
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 18:20, s. 3942-3954
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Tidskriftsartikel (refereegranskat)abstract
- Huntington's disease is a severe progressive neurodegenerative disorder caused by a CAG-expansion in the IT15 gene, which encodes huntingtin. The disease primarily affects the neostriatum and cerebral cortex and also associates with increased incidence of diabetes. Here, we show that mutant huntingtin disrupts intracellular transport and insulin secretion by direct interference with microtubular beta-tubulin. We demonstrate that mutant huntingtin impairs glucose-stimulated insulin secretion in insulin-producing beta-cells, without altering stored levels of insulin. Using VSVG-YFP, we show that mutant huntingtin retards post-Golgi transport. Moreover, we demonstrate that the speed of insulin vesicle trafficking is reduced. Using immunoprecipitation of mutant and wild-type huntingtin in combination with mass spectrometry, we reveal an enhanced and aberrant interaction between mutant huntingtin and beta-tubulin, implying the underlying mechanism of impaired intracellular transport. Thus, our findings have revealed a novel pathogenetic process by which mutant huntingtin may disrupt hormone exocytosis from beta-cells and possibly impair vesicular transport in any cell that expresses the pathogenic protein.
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| 2. |
- Araujo, IM, et al.
(författare)
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Calpain activation is involved in early caspase-independent neurodegeneration in the hippocampus following status epilepticus
- 2008
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 105:3, s. 666-676
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Tidskriftsartikel (refereegranskat)abstract
- Evidence for increased calpain activity has been described in the hippocampus of rodent models of temporal lobe epilepsy. However, it is not known whether calpains are involved in the cell death that accompanies seizures. In this work, we characterized calpain activation by examining the proteolysis of calpain substrates and in parallel we followed cell death in the hippocampus of epileptic rats. Male Wistar rats were injected with kainic acid (KA; 10 mg/kg) intraperitoneally and sacrificed 24h later, after development of grade 5 seizures. We observed a strong Fluoro-Jade labelling in the CA1 and CA3 areas of the hippocampus in the rats that received KA, as compared to saline-treated rats. Immunohistochemistry and Western blot analysis for the calpain-derived breakdown products of spectrin (SBDP) showed evidence of increased calpain activity in the same regions of the hippocampus where cell death is observed. No evidence was found for caspase activation, in the same conditions. Treatment with the calpain inhibitor MDL 28170 significantly prevented the neurodegeneration observed in CA1. Taken together, our data suggest that early calpain activation, but not caspase activation, is involved in neurotoxicity in the hippocampus after status epilepticus.
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| 3. |
- Björkqvist, Maria, et al.
(författare)
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A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease.
- 2008
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 205, s. 1869-1877
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Tidskriftsartikel (refereegranskat)abstract
- Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities. We examined the peripheral immune system and found widespread evidence of innate immune activation detectable in plasma throughout the course of HD. Interleukin 6 levels were increased in HD gene carriers with a mean of 16 years before the predicted onset of clinical symptoms. To our knowledge, this is the earliest plasma abnormality identified in HD. Monocytes from HD subjects expressed mutant huntingtin and were pathologically hyperactive in response to stimulation, suggesting that the mutant protein triggers a cell-autonomous immune activation. A similar pattern was seen in macrophages and microglia from HD mouse models, and the cerebrospinal fluid and striatum of HD patients exhibited abnormal immune activation, suggesting that immune dysfunction plays a role in brain pathology. Collectively, our data suggest parallel central nervous system and peripheral pathogenic pathways of immune activation in HD.
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| 4. |
- Deierborg, Tomas, et al.
(författare)
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Emerging restorative treatments for Parkinson's disease.
- 2008
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Ingår i: Progress in Neurobiology. - : Elsevier BV. - 1873-5118 .- 0301-0082. ; 85, s. 407-432
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Tidskriftsartikel (refereegranskat)abstract
- Several exciting approaches for restorative therapy in Parkinson's disease have emerged over the past two decades. This review initially describes experimental and clinical data regarding growth factor administration. We focus on glial cell line-derived neurotrophic factor (GDNF), particularly its role in neuroprotection and in regeneration in Parkinson's disease. Thereafter, we discuss the challenges currently facing cell transplantation in Parkinson's disease and briefly consider the possibility to continue testing intrastriatal transplantation of fetal dopaminergic progenitors clinically. We also give a more detailed overview of the developmental biology of dopaminergic neurons and the potential of certain stem cells, i.e. neural and embryonic stem cells, to differentiate into dopaminergic neurons. Finally, we discuss adult neurogenesis as a potential tool for restoring lost dopamine neurons in patients suffering from Parkinson's disease.
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| 5. |
- Lane, Emma, et al.
(författare)
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Neuroinflammation in the generation of post-transplantation dyskinesia in Parkinson's disease.
- 2008
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 32, s. 220-228
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Tidskriftsartikel (refereegranskat)abstract
- The observation that neural grafts can induce dyskinesias has severely hindered the development of a transplantation therapy for Parkinson's disease (PD). We addressed the hypothesis that inflammatory responses within and around an intrastriatal graft containing dopamine neurons can trigger dyskinetic behaviors. We subjected rats to unilateral nigrostriatal lesions with 6-hydroxydopamine (6-OHDA) and treated them with L-DOPA for 21 days in order to induce abnormal involuntary movements (AIMs). Subsequently, we grafted the rats with allogeneic embryonic ventral mesencephalic tissue in the dopamine-denervated striatum. In agreement with earlier studies, the grafted rats developed dyskinesia-like AIMs in response to amphetamine. We then used two experimental approaches to induce an inflammatory response and examined if the amphetamine-induced AIMs worsened or if spontaneous AIMs developed. In one experiment, we challenged the neural graft hosts immunologically with an orthotopic skin allograft of the same genetic origin as the intracerebral neural allograft. In another experiment, we infused the pro-inflammatory cytokine interleukin 2 (IL-2) adjacent to the intrastriatal grafts using osmotic minipumps. The skin allograft induced rapid rejection of the mesencephalic allografts, leading to disappearance of the amphetamine-induced AIMs. Contrary to our hypothesis, the rejection process itself did not elicit AIMs. Likewise, the IL-2 infusion did not induce spontaneous AIMs, nor did it alter L-DOPA-induced AIMs. The IL-2 infusions did, however, elicit the predicted marked striatal inflammation, as evidenced by the presence of activated microglia and IL2Ralpha-positive cells. These results indicate that an inflammatory response in and around grafted dopaminergic neurons is not sufficient to evoke dyskinetic behaviors in experimental models of PD.
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| 6. |
- Li, Jia-Yi, et al.
(författare)
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Critical issues of clinical human embryonic stem cell therapy for brain repair.
- 2008
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Ingår i: Trends in Neurosciences. - : Elsevier BV. - 1878-108X .- 0166-2236. ; 31, s. 146-153
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Tidskriftsartikel (refereegranskat)abstract
- Embryonic stem cells (ESCs) provide hope as a potential regenerative therapy for neurological conditions such as Parkinson's disease and spinal cord injury. Currently, ESC-based nervous system repair faces several problems. One major hurdle is related to problems in generating large and defined populations of the desired types of neurons from human ESCs (hESCs). Moreover, survival of grafted hESC-derived cells has varied and functional recovery in recipient animals has often been disappointing. Importantly, in clinical trials, adverse effects after surgery, including tumors or vigorous immune reactions, must be avoided. Here we highlight attempts to overcome these hurdles with hESCs intended for central nervous system repair. We focus on hESC-derived dopamine-producing neurons that can be grafted in Parkinson's disease and identify critical experiments that need to be conducted before clinical trials can occur.
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| 7. |
- Li, Jia-Yi, et al.
(författare)
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Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation.
- 2008
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 14, s. 501-503
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Tidskriftsartikel (refereegranskat)abstract
- Two subjects with Parkinson's disease who had long-term survival of transplanted fetal mesencephalic dopaminergic neurons (11-16 years) developed alpha-synuclein-positive Lewy bodies in grafted neurons. Our observation has key implications for understanding Parkinson's pathogenesis by providing the first evidence, to our knowledge, that the disease can propagate from host to graft cells. However, available data suggest that the majority of grafted cells are functionally unimpaired after a decade, and recipients can still experience long-term symptomatic relief.
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