| 1. |
- Lotharius, Julie, et al.
(författare)
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Effect of mutant alpha-synuclein on dopamine homeostasis in a new human mesencephalic cell line.
- 2002
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Ingår i: Journal of Biological Chemistry. - 1083-351X .- 0021-9258. ; 277:41, s. 38884-38894
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in alpha-synuclein have been linked to rare, autosomal dominant forms of Parkinsons disease. Despite its ubiquitous expression, mutant alpha-synuclein primarily leads to the loss of dopamine-producing neurons in the substantia nigra. Alpha-synuclein is a presynaptic nerve terminal protein of unknown function, though some studies suggest it is important for synapse formation and maintenance. The present study utilized a new human mesencephalic cell line, MESC2.10, to study the effect of A53T mutant alpha-synuclein on dopamine homeostasis. In addition to expressing markers of mature dopamine neurons, differentiated MESC2.10 cells are electrically active, produce dopamine, and express wild-type human alpha-synuclein. Lentivirus-induced overexpression of A53T mutant alpha-synuclein in differentiated MESC2.10 cells resulted in downregulation of the vesicular dopamine transporter (VMAT2), decreased potassium-induced and increased amphetamine-induced dopamine release, enhanced cytoplasmic dopamine immunofluorescence, and increased intracellular levels of superoxide. These results suggest that mutant alpha-synuclein leads to an impairment in vesicular dopamine storage and consequent accumulation of dopamine in the cytosol, a pathogenic mechanism that underlies the toxicity of the psychostimulant amphetamine and the parkinsonian neurotoxin 1-methyl-4-phenylpyridinium. Interestingly, cells expressing A53T mutant alpha-synuclein were resistant to amphetamine-induced toxicity. Since extra-vesicular, cytoplasmic dopamine can be easily oxidized into reactive oxygen species and other toxic metabolites, mutations in alpha-synuclein might lead to Parkinsons disease by triggering protracted, low-grade dopamine toxicity resulting in terminal degeneration and ultimately cell death.
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| 2. |
- Lotharius, Julie, et al.
(författare)
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Impaired dopamine storage resulting from alpha-synuclein mutations may contribute to the pathogenesis of Parkinson's disease.
- 2002
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 11:20, s. 2395-2407
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Forskningsöversikt (refereegranskat)abstract
- Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the inability to initiate, execute and control movement. Neuropathologically, there is a striking loss of dopamine-producing neurons in the substantia nigra pars compacta, accompanied by depletion of dopamine in the striatum. Most forms of PD are sporadic, though in some cases familial inheritance is observed. In the late 1990s, two mutations in the alpha-synuclein gene were linked to rare, autosomal dominant forms of PD. Previously cloned from cholinergic vesicles of the Torpedo electric ray, alpha-synuclein is highly enriched in presynaptic nerve terminals and appears to be involved in synapse maintenance and plasticity. It is expressed ubiquitously in the brain, raising the important question of why dopaminergic neurons are primarily targeted in persons carrying mutations in alpha-synuclein. In this article, we review the current literature on alpha-synuclein and suggest a possible role for this protein in vesicle recycling via its regulation of phospholipase D2, its fatty acid-binding properties, or both. Exogenous application of dopamine, as well as redistribution of vesicular dopamine to the cytoplasm, can be toxic to dopaminergic neurons. Thus, impaired neurotransmitter storage arising from mutations in alpha-synuclein could lead to cytoplasmic accumulation of dopamine. The breakdown of this labile neurotransmitter in the cytoplasm could, in turn, promote oxidative stress and metabolic dysfunction, both of which have been observed in nigral tissue from PD patients.
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| 3. |
- Lotharius, Julie, et al.
(författare)
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Pathogenesis of Parkinson's disease: dopamine, vesicles and alpha-synuclein.
- 2002
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Ingår i: Nature Reviews Neuroscience. - : Springer Science and Business Media LLC. - 1471-003X .- 1471-0048. ; 3:12, s. 932-942
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Forskningsöversikt (refereegranskat)abstract
- Parkinson's disease is a devastating neurological condition that affects at least four million people. A striking feature of this disorder is the preferential loss of dopamine-producing neurons in the midbrain. Several aetiological triggers have been linked to Parkinson's disease, including genetic mutations and environmental toxins, but the pathway that leads to cell death is unknown. Recent developments have shed light on the pathogenic mechanisms that underlie the degeneration of these cells. We propose that defective sequestration of dopamine into vesicles, leading to the generation of reactive oxygen species in the cytoplasm, is a key event in the demise of dopaminergic neurons in Parkinson's disease, and might represent a common pathway that underlies both genetic and sporadic forms of the disorder.
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| 4. |
- O'Malley, KL, et al.
(författare)
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Targeted expression of BCL-2 attenuates MPP+ but not 6-OHDA induced cell death in dopaminergic neurons
- 2003
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Ingår i: Neurobiology of Disease. - 0969-9961. ; 14:1, s. 43-51
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Tidskriftsartikel (refereegranskat)abstract
- Neurodegenerative diseases such as Parkinson's disease exhibit complex features of cell death reflecting both the primary lesion as well as surrounding interconnected events. Because Bcl-2 family members are intimately involved in cell death processes, the present Study used dopaminergic cultures from control, Bcl-2-overexpressing, or Bax-deficient genetically modified animals to determine the in situ effects of parkinsonism-inducing toxins. MPP+-mediated cell death was attenuated by Bcl-2 but did not require Bax. Accordingly, mutations or deletions within Bax heterodimerization domains, BH1, BH2, or BH3 had no effect on Bcl-2's ability to prevent cell death. whereas the cell-death suppressing BH4 domain did. Although both staurosporine and 6-OHDA induced apoptosis, overexpression of Bcl-2 only rescued cells from programmed cell death induced by staurosporine. Thus, differential cell death pathways are associated with these cytotoxic signals in primary models of Parkinson's disease. (C) 2003 Elsevier Science (USA). All rights reserved.
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| 5. |
- Petersén, Åsa, et al.
(författare)
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Evidence for Dysfunction of the Nigrostriatal Pathway in the R6/1 Line of Transgenic Huntington's Disease Mice.
- 2002
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 11:1, s. 134-146
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Tidskriftsartikel (refereegranskat)abstract
- The present multidisciplinary study examined nigrostriatal dopamine and striatal amino acid transmission in the R6/1 line of transgenic Huntington's disease (HD) mice expressing exon 1 of the HD gene with 115 CAG repeats. Although the number of tyrosine hydroxylase-positive neurons was not reduced and nigrostriatal connectivity remained intact in 16-week-old R6/1 mice, the size of tyrosine hydroxylase-positive neurons in the substantia nigra was reduced by 15%, and approximately 30% of these cells exhibited aggregated huntingtin. In addition, using in vivo microdialysis, we found that basal extracellular striatal dopamine levels were reduced by 70% in R6/1 mice compared to their wild-type littermates. Intrastriatal perfusion with malonate in R6/1 mice resulted in a short-lasting, attenuated increase in local dopamine release compared to wild-type mice. Furthermore, the size of the malonate-induced striatal lesion was 80% smaller in these animals. Taken together, these findings suggest that a functional deficit in nigrostriatal dopamine transmission may contribute to the behavioral phenotype and the resistance to malonate-induced neurotoxicity characteristic of R6/1 HD mice.
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| 6. |
- Smith, Ruben, et al.
(författare)
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Fria radikaler och sjuka proteiner - bovarna bakom Parkinsons sjukdom?[Free radicals and ailing proteins - the culprits behind Parkinson’s disease?]
- 2003
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Ingår i: Läkartidningen. - 0023-7205. ; 100:15, s. 6-1329
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Tidskriftsartikel (refereegranskat)abstract
- Parkinson’s disease is one of the most common neurodegenerative diseases, and affects approximately 1% of the population over 65 years of age. Many different insults appear to be involved in the etiology of the disease, among them environmental toxins and mitochondrial dysfunction. During the past five years, mutations in five different genes have been linked to rare, familial forms of Parkinson’s disease. One of the mutated proteins, a-synuclein is normally implicated in synaptic plasticity and vesicle function. Dysfunction of this protein might lead to increased cytoplasmic dopamine levels. Since cytoplasmic dopamine is readily prone to autooxidation and enzymatic degradation - processes which generate reactive oxygen species - failure to properly store dopamine into vesicles might lead to oxidative stress. Indeed, nigral tissue from idiopathic Parkinson’s disease patients shows signs of oxidative damage. In this article we propose that dopamine-induced oxidative stress might be a common final pathway in the pathogenesis of the disease.
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