Fatal attractions: abnormal protein aggregation and neuron death in Parkinson's disease and Lewy body dementia

Trojanowski, John Q.; Goedert, Michel; Iwatsubo, Takeshi; Lee, Virginia M.‐Y.

doi:10.1038/sj.cdd.4400432

Cited by 269 publications

(188 citation statements)

References 45 publications

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“…Furthermore, we tested AMPH-induced toxicity in human mesencephalic neurons, while other groups measured DA-and 6-OHDA-mediated toxicity in either nondopaminergic cells (e.g. HEK293) (54) or rat mesencephalic cells (53). Studies by Zhou and colleagues (44,59) demonstrate that the pathogenicity of A53TSYN is not only dependent on the cell type used but on the species in which the mutant protein is expressed.…”

Section: Discussionmentioning

confidence: 99%

Effect of Mutant α-Synuclein on Dopamine Homeostasis in a New Human Mesencephalic Cell Line

Lotharius¹,

Barg²,

Wiekop³

et al. 2002

Journal of Biological Chemistry

311

266

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Mutations in ␣-synuclein have been linked to rare, autosomal dominant forms of Parkinson's disease. Despite its ubiquitous expression, mutant ␣-synuclein primarily leads to the loss of dopamine-producing neurons in the substantia nigra. ␣-Synuclein is a presynaptic nerve terminal protein of unknown function, although several studies suggest it is important for synaptic plasticity and maintenance. The present study utilized a new human mesencephalic cell line, MESC2.10, to study the effect of A53T mutant ␣-synuclein on dopamine homeostasis. In addition to expressing markers of mature dopamine neurons, differentiated MESC2.10 cells are electrically active, produce dopamine, and express wildtype human ␣-synuclein. Lentivirus-induced overexpression of A53T mutant ␣-synuclein in differentiated MESC2.10 cells resulted in down-regulation 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 ␣-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 ␣-synuclein were resistant to amphetamine-induced toxicity. Because extravesicular, cytoplasmic dopamine can be easily oxidized into reactive oxygen species and other toxic metabolites, mutations in ␣-synuclein might lead to Parkinson's disease by triggering protracted, low grade dopamine toxicity resulting in terminal degeneration and ultimately cell death.

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Section: Discussionmentioning

confidence: 99%

Effect of Mutant α-Synuclein on Dopamine Homeostasis in a New Human Mesencephalic Cell Line

Lotharius¹,

Barg²,

Wiekop³

et al. 2002

Journal of Biological Chemistry

311

266

View full text Add to dashboard Cite

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“…Protein aggregation is a common hallmark of neurodegenerative disease (Harper & Lansbury, 1997; Trojanowski et al , 1998; Koo et al , 1999; Aguzzi & O'Connor, 2010) although the mechanisms of toxicity remain poorly understood. Different neurodegenerative diseases, or their subtypes, are often distinguished by the specific patterns of protein aggregation.…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity

et al. 2017

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Neuronal inclusions of aggregated RNA‐binding protein fused in sarcoma (FUS) are hallmarks of ALS and frontotemporal dementia subtypes. Intriguingly, FUS's nearly uncharged, aggregation‐prone, yeast prion‐like, low sequence‐complexity domain (LC) is known to be targeted for phosphorylation. Here we map in vitro and in‐cell phosphorylation sites across FUS LC. We show that both phosphorylation and phosphomimetic variants reduce its aggregation‐prone/prion‐like character, disrupting FUS phase separation in the presence of RNA or salt and reducing FUS propensity to aggregate. Nuclear magnetic resonance spectroscopy demonstrates the intrinsically disordered structure of FUS LC is preserved after phosphorylation; however, transient domain collapse and self‐interaction are reduced by phosphomimetics. Moreover, we show that phosphomimetic FUS reduces aggregation in human and yeast cell models, and can ameliorate FUS‐associated cytotoxicity. Hence, post‐translational modification may be a mechanism by which cells control physiological assembly and prevent pathological protein aggregation, suggesting a potential treatment pathway amenable to pharmacologic modulation.

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“…1 However, it might be necessary to develop alternative gene therapy approaches in view of increasing evidence that favors a potential role for abnormal aggregation of a-synuclein in the central nervous system (CNS) as one of the central mechanisms involved in the pathogenesis of PD and DLB. [3][4][5] a-Synuclein is capable of selfaggregating to form both oligomers and polymers. [6][7][8] Toxic oligomers form protofibrils that can potentially damage the cell membrane and promote neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

An antiaggregation gene therapy strategy for Lewy body disease utilizing β-synuclein lentivirus in a transgenic model

et al. 2004

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Current experimental gene therapy approaches for Parkinson's disease (PD) and dementia with Lewy bodies (DLB) include the use of viral vectors expressing antiapoptosis genes, neurotrophic factors and dopaminergic system enzymes. However, since increasing evidence favors a role for a-synuclein accumulation in the pathogenesis of these disorders, an alternative therapy might require the transfer of genes that might block a-synuclein accumulation. b-Synuclein, the nonamyloidogenic homologue of a-synuclein, has recently been identified as a potential candidate. Thus, in vivo transfer of genes encoding b-synuclein might provide a novel approach to the development of experimental treatments for PD and DLB. To assess this possibility and to better understand the mechanisms involved, a lentiviral vector expressing human (h) b-synuclein (lenti-b-synuclein) was tested in a transgenic (tg) mouse model of ha-synuclein aggregation. This study showed that unilateral intracerebral injection of lenti-b-synuclein reduced the formation of hasynuclein inclusions and the accumulation of ha-synuclein in synapses and ameliorated the neurodegenerative alterations in the tg mice. Both in vivo and in vitro coimmunoprecipitation and immunoblot experiments show that the mechanisms of b-synuclein neuroprotection involve binding of this molecule to ha-synuclein and Akt, resulting in the decreased aggregation and accumulation of ha-synuclein in the synaptic membrane. Together, these data further support a role for b-synuclein in regulating the conformational state of a-synuclein and suggest that this gene transfer approach might have potential for the development of alternative therapies for PD and DLB.

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Fatal attractions: abnormal protein aggregation and neuron death in Parkinson's disease and Lewy body dementia

Cited by 269 publications

References 45 publications

Effect of Mutant α-Synuclein on Dopamine Homeostasis in a New Human Mesencephalic Cell Line

Effect of Mutant α-Synuclein on Dopamine Homeostasis in a New Human Mesencephalic Cell Line

Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity

An antiaggregation gene therapy strategy for Lewy body disease utilizing β-synuclein lentivirus in a transgenic model

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