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1.
Mov Disord ; 34(2): 167-179, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30633814

RESUMO

Parkinson's disease (PD) is primarily a movement disorder driven by the loss of dopamine-producing neurons in the substantia nigra (SN). Early identification of the oxidative properties of dopamine implicated it as a potential source of oxidative stress in PD, yet few studies have investigated dopamine neurotoxicity in vivo. The discovery of PD-causing mutations in α-synuclein and the presence of aggregated α-synuclein in the hallmark Lewy body pathology of PD revealed another important player. Despite extensive efforts, the precise role of α-synuclein aggregation in neurodegeneration remains unclear. We recently manipulated both dopamine levels and α-synuclein expression in aged mice and found that only the combination of these 2 factors caused progressive neurodegeneration of the SN and an associated motor deficit. Dopamine modified α-synuclein aggregation in the SN, resulting in greater abundance of α-synuclein oligomers and unique dopamine-induced oligomeric conformations. Furthermore, disruption of the dopamine-α-synuclein interaction rescued dopaminergic neurons from degeneration in transgenic Caenorhabditis elegans models. In this Perspective, we discuss these findings in the context of known α-synuclein and dopamine biology, review the evidence for α-synuclein oligomer toxicity and potential mechanisms, and discuss therapeutic implications. © 2019 International Parkinson and Movement Disorder Society.


Assuntos
Dopamina/metabolismo , Degeneração Neural/metabolismo , Degeneração Neural/patologia , alfa-Sinucleína/metabolismo , Animais , Neurônios Dopaminérgicos/metabolismo , Humanos , Estresse Oxidativo/fisiologia , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia
2.
Biochemistry ; 56(5): 683-691, 2017 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-28045494

RESUMO

Fibrillar aggregates of the protein α-synuclein (αS) are one of the hallmarks of Parkinson's disease. Here, we show that measuring the fluorescence polarization (FP) of labels at several sites on αS allows one to monitor changes in the local dynamics of the protein after binding to micelles or vesicles, and during fibril formation. Most significantly, these site-specific FP measurements provide insight into structural remodeling of αS fibrils by small molecules and have the potential for use in moderate-throughput screens to identify small molecules that could be used to treat Parkinson's disease.


Assuntos
Catequina/análogos & derivados , Dopamina/química , Masoprocol/química , Agregados Proteicos/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , alfa-Sinucleína/química , Sequência de Aminoácidos , Catequina/química , Catequina/farmacologia , Dopamina/farmacologia , Polarização de Fluorescência , Corantes Fluorescentes/química , Humanos , Masoprocol/metabolismo , Fosfatidilcolinas/química , Proteínas Recombinantes/química , Bibliotecas de Moléculas Pequenas/farmacologia , Dodecilsulfato de Sódio/química , Lipossomas Unilamelares/química , Xantenos/química
3.
Neurobiol Dis ; 88: 66-74, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26747212

RESUMO

α-Synuclein is a conserved, abundantly expressed protein that is partially localized in pre-synaptic terminals in the central nervous system. The precise biological function(s) and structure of α-synuclein are under investigation. Recently, the native conformation and the presence of naturally occurring multimeric assemblies have come under debate. These are important deliberations because α-synuclein assembles into highly organized amyloid-like fibrils and non-amyloid amorphous aggregates that constitute the neuronal inclusions in Parkinson's disease and related disorders. Therefore understanding the nature of the native and pathological conformations is pivotal from the standpoint of therapeutic interventions that could maintain α-synuclein in its physiological state. In this review, we will discuss the existing evidence that define the physiological states of α-synuclein and highlight how the inherent structural flexibility of this protein may be important in health and disease.


Assuntos
Modelos Químicos , Dinâmica não Linear , alfa-Sinucleína/química , alfa-Sinucleína/metabolismo , Animais , Humanos , Conformação Proteica
4.
Sci Rep ; 9(1): 2937, 2019 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-30814575

RESUMO

Growing evidence implicates α-synuclein aggregation as a key driver of neurodegeneration in Parkinson's disease (PD) and other neurodegenerative disorders. Herein, the molecular and structural mechanisms of inhibiting α-synuclein aggregation by novel analogs of nordihydroguaiaretic acid (NDGA), a phenolic dibenzenediol lignan, were explored using an array of biochemical and biophysical methodologies. NDGA analogs induced modest, progressive compaction of monomeric α-synuclein, preventing aggregation into amyloid-like fibrils. This conformational remodeling preserved the dynamic adoption of α-helical conformations, which are essential for physiological membrane interactions. Oxidation-dependent NDGA cyclization was required for the interaction with monomeric α-synuclein. NDGA analog-pretreated α-synuclein did not aggregate even without NDGA-analogs in the aggregation mixture. Strikingly, NDGA-pretreated α-synuclein suppressed aggregation of naïve untreated aggregation-competent monomeric α-synuclein. Further, cyclized NDGA reduced α-synuclein-driven neurodegeneration in Caenorhabditis elegans. The cyclized NDGA analogs may serve as a platform for the development of small molecules that stabilize aggregation-resistant α-synuclein monomers without interfering with functional conformations yielding potential therapies for PD and related disorders.


Assuntos
Amiloide/metabolismo , Masoprocol/farmacologia , Doença de Parkinson/patologia , Agregação Patológica de Proteínas/tratamento farmacológico , alfa-Sinucleína/metabolismo , Animais , Caenorhabditis elegans/metabolismo , Membrana Celular/metabolismo , Humanos , Masoprocol/análogos & derivados , Masoprocol/metabolismo , Fosfolipídeos/metabolismo , Agregação Patológica de Proteínas/patologia
5.
EBioMedicine ; 31: 307-319, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29759483

RESUMO

Accumulation of aggregated α-synuclein into Lewy bodies is thought to contribute to the onset and progression of dopaminergic neuron degeneration in Parkinson's disease (PD) and related disorders. Although protein aggregation is associated with perturbation of proteostasis, how α-synuclein aggregation affects the brain proteome and signaling remains uncertain. In a mouse model of α-synuclein aggregation, 6% of 6215 proteins and 1.6% of 8183 phosphopeptides changed in abundance, indicating conservation of proteostasis and phosphorylation signaling. The proteomic analysis confirmed changes in abundance of proteins that regulate dopamine synthesis and transport, synaptic activity and integrity, and unearthed changes in mRNA binding, processing and protein translation. Phosphorylation signaling changes centered on axonal and synaptic cytoskeletal organization and structural integrity. Proteostatic responses included a significant increase in the levels of Lmp7, a component of the immunoproteasome. Increased Lmp7 levels and activity were also quantified in postmortem human brains with PD and dementia with Lewy bodies. Functionally, the immunoproteasome degrades α-synuclein aggregates and generates potentially antigenic peptides. Expression and activity of the immunoproteasome may represent testable targets to induce adaptive responses that maintain proteome integrity and modulate immune responses in protein aggregation disorders.


Assuntos
Doença de Parkinson/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Agregação Patológica de Proteínas/metabolismo , Proteostase , alfa-Sinucleína/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Knockout , Doença de Parkinson/genética , Doença de Parkinson/patologia , Complexo de Endopeptidases do Proteassoma/genética , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/patologia , alfa-Sinucleína/genética
6.
Nat Neurosci ; 20(11): 1560-1568, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28920936

RESUMO

Parkinson's disease (PD) is defined by the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy body inclusions containing aggregated α-synuclein. Efforts to explain dopamine neuron vulnerability are hindered by the lack of dopaminergic cell death in α-synuclein transgenic mice. To address this, we manipulated both dopamine levels and α-synuclein expression. Nigrally targeted expression of mutant tyrosine hydroxylase with enhanced catalytic activity increased dopamine levels without damaging neurons in non-transgenic mice. In contrast, raising dopamine levels in mice expressing human A53T mutant α-synuclein induced progressive nigrostriatal degeneration and reduced locomotion. Dopamine elevation in A53T mice increased levels of potentially toxic α-synuclein oligomers, resulting in conformationally and functionally modified species. Moreover, in genetically tractable Caenorhabditis elegans models, expression of α-synuclein mutated at the site of interaction with dopamine prevented dopamine-induced toxicity. These data suggest that a unique mechanism links two cardinal features of PD: dopaminergic cell death and α-synuclein aggregation.


Assuntos
Corpo Estriado/metabolismo , Dopamina/biossíntese , Neurônios Dopaminérgicos/metabolismo , Doenças Neurodegenerativas/metabolismo , Substância Negra/metabolismo , alfa-Sinucleína/biossíntese , Animais , Caenorhabditis elegans , Células Cultivadas , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Feminino , Humanos , Levodopa/farmacologia , Levodopa/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/patologia , Substância Negra/efeitos dos fármacos , Substância Negra/patologia
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