Molecular Insights into the Interaction between α-Synuclein and Docosahexaenoic Acid

Franceschi, Giorgia De; Frare, Erica; Bubacco, Luigi; Mammi, Stefano; Fontana, Angelo; Laureto, Patrizia Polverino de

doi:10.1016/j.jmb.2009.09.008

Cited by 64 publications

(94 citation statements)

References 87 publications

(123 reference statements)

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“…Briefly 2 mg/ml purified synuclein was sedimented at three speeds (10,000, 14,000, and 20,000 rpm, AN-60 rotor) in a Beckman XL-1 ultracentrifuge for 16 -20 h per speed at 20°C, and protein concentration as a function of radius was determined by absorbance at 280 nm. Sedimentation curves were globally fit with Sedphit and Sedphat software (National Institutes of Health), using the monomer-dimer model with the dimer K d value set to zero, and an extinction coefficient for synuclein of 5960 M Ϫ1 cm Ϫ1 (38). Dynamic Light Scattering-Dynamic light scattering of protein was measured with a DynaPro molecular sizing instrument (Protein Solutions, Lakewood, NJ) in micro quartz cuvettes with 1.5-mm path length and 12-ml volume.…”

Section: Protein Analysismentioning

confidence: 99%

Direct Membrane Association Drives Mitochondrial Fission by the Parkinson Disease-associated Protein α-Synuclein

Nakamura

Nemani

Azarbal

et al. 2011

Journal of Biological Chemistry

531

556

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The protein ␣-synuclein has a central role in Parkinson disease, but the mechanism by which it contributes to neural degeneration remains unknown. We now show that the expression of ␣-synuclein in mammalian cells, including neurons in vitro and in vivo, causes the fragmentation of mitochondria. The effect is specific for synuclein, with more fragmentation by ␣-than ␤-or ␥-isoforms, and it is not accompanied by changes in the morphology of other organelles or in mitochondrial membrane potential. However, mitochondrial fragmentation is eventually followed by a decline in respiration and neuronal death. The fragmentation does not require the mitochondrial fission protein Drp1 and involves a direct interaction of synuclein with mitochondrial membranes. In vitro, synuclein fragments artificial membranes containing the mitochondrial lipid cardiolipin, and this effect is specific for the small oligomeric forms of synuclein. ␣-Synuclein thus exerts a primary and direct effect on the morphology of an organelle long implicated in the pathogenesis of Parkinson disease.Many observations have implicated mitochondria in the pathogenesis of PD.2 Mitochondria from the substantia nigra of affected patients show a selective reduction in the activity of respiratory chain complex I (1). Somatic mutations also accumulate with age and PD in the mitochondrial DNA of substantia nigra neurons (2). In addition, the neurotoxins MPTP and rotenone, which produce models of PD, both act by disrupting mitochondrial function. Genetic evidence further supports a primary role for mitochondria in the pathogenesis of PD. Mutations in parkin and the mitochondrial kinase PINK1 both cause autosomal recessive PD (3), and these genes appear required for the normal clearance of defective mitochondria by autophagy (4). However, the molecular mechanisms responsible for mitochondrial dysfunction in the much more common sporadic forms of PD have remained unclear. Several observations suggest a central role for the protein ␣-synuclein in the pathogenesis of sporadic PD. Point mutations in synuclein produce a rare autosomal dominant form of PD (5-7), indicating a causative role for the protein. ␣-Synuclein also accumulates in the Lewy bodies and dystrophic neurites of essentially all patients with idiopathic PD (8), implicating the protein in sporadic as well as familial forms of the disease. Furthermore, duplication and particularly triplication of the SNCA (␣-synuclein) gene cause a severe, highly penetrant form of PD (9, 10), indicating a dose-dependent pathogenic role for the wild type protein when overexpressed and suggesting that the accumulation of synuclein in sporadic PD is the primary pathogenic event. However, the mechanism by which ␣-synuclein causes PD remains poorly understood. Expressed in yeast and Drosophila, human ␣-synuclein produces severe toxicity (11-14), but these model organisms lack endogenous synuclein, and the overexpression of wild type synuclein in mammalian systems causes remarkably little if any consistent toxicity (15-18).Althou...

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Section: Protein Analysismentioning

confidence: 99%

Direct Membrane Association Drives Mitochondrial Fission by the Parkinson Disease-associated Protein α-Synuclein

Nakamura

Nemani

Azarbal

et al. 2011

Journal of Biological Chemistry

531

556

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“…We previously observed a mutual effect in the interaction between monomeric ␣-syn and DHA in vitro (23). DHA is induced to form small oil droplets.…”

mentioning

confidence: 96%

Structural and Morphological Characterization of Aggregated Species of α-Synuclein Induced by Docosahexaenoic Acid

Franceschi

Frare

Pivato

et al. 2011

Journal of Biological Chemistry

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101

116

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The interaction of brain lipids with ␣-synuclein may play an important role in the pathogenesis of Parkinson disease (PD). Docosahexaenoic acid (DHA) is an abundant fatty acid of neuronal membranes, and it is presents at high levels in brain areas with ␣-synuclein inclusions of patients with PD. In animal models, an increase of DHA content in the brain induces ␣-synuclein oligomer formation in vivo. However, it is not clear whether these oligomeric species are the precursors of the larger aggregates found in Lewy bodies of post-mortem PD brains. To characterize these species and to define the role of fatty acids in amyloid formation, we investigated the aggregation process of ␣-synuclein in the presence of DHA. We found that DHA readily promotes ␣-synuclein aggregation and that the morphology of these aggregates is dependent on the ratio between the protein and DHA. In the presence of a molar ratio protein/DHA of 1:10, amyloid-like fibrils are formed. These fibrils are morphologically different from those formed by ␣-synuclein alone and have a less packed structure. At a protein/DHA molar ratio of 1:50, we observe the formation of stable oligomers. Moreover, chemical modifications, methionine oxidations, and proteinlipid adduct formations are induced by increasing concentrations of DHA. The extent of these modifications defines the structure and the stability of aggregates. We also show that ␣-synuclein oligomers are more toxic if generated in the presence of DHA in dopaminergic neuronal cell lines, suggesting that these species might be important in the neurodegenerative process associated with PD.

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“…97 A α-sinucleína é uma proteína desdobrada caracterizada por sete repetições (KTKEGV) na região N-terminal; por uma região central hidrofóbica formada por resíduos 61-65 ( componente não β-amiloide); e por trechos acídicos na parte C-terminal. 98 Alguns estudos reportam que α-sinucleína pode interagir com ácidos graxos poli-insaturados, cuja interação promoveria a oligomerização da proteína. 95,96,98,99 Os níveis de DHA mostraram-se elevados nas áreas do cérebro contendo α-sinucleína em pacientes com PD, o que atraiu o interesse no estudo da interação entre DHA e α-sinucleína.…”

Section: Doença De Parkinson (Pd)unclassified

“…98 Alguns estudos reportam que α-sinucleína pode interagir com ácidos graxos poli-insaturados, cuja interação promoveria a oligomerização da proteína. 95,96,98,99 Os níveis de DHA mostraram-se elevados nas áreas do cérebro contendo α-sinucleína em pacientes com PD, o que atraiu o interesse no estudo da interação entre DHA e α-sinucleína. 98,100 De Francheschi e colaboradores 98 mostraram que α-sinucleína interage com o DHA adquirindo uma conformação α-helicoidal e o estado físico do lipídio torna-se alterado.…”

Section: Doença De Parkinson (Pd)unclassified

“…95,96,98,99 Os níveis de DHA mostraram-se elevados nas áreas do cérebro contendo α-sinucleína em pacientes com PD, o que atraiu o interesse no estudo da interação entre DHA e α-sinucleína. 98,100 De Francheschi e colaboradores 98 mostraram que α-sinucleína interage com o DHA adquirindo uma conformação α-helicoidal e o estado físico do lipídio torna-se alterado. Especificamente, métodos biofísicos e microscopia eletrônica indicaram que o DHA forma gotículas de óleo na presença da α-sinucleína.…”

Section: Doença De Parkinson (Pd)unclassified

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Metabolismo, oxidação e implicações biológicas do ácido docosahexaenoico em doenças neurodegenerativas

Appolinário¹,

Derogis²,

Yamaguti³

et al. 2011

Quím. Nova

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Recebido em 16/8/10; aceito em 20/4/11; publicado na web em 8/7/11 METABOLISM, OXIDATION AND BIOLOGICAL IMPLICATIONS OF DOCOSAHEXAENOIC ACID IN NEURODEGENERATIVE DISEASES. Docosahexaenoic acid (C22:6, n-3, DHA) is a polyunsaturated fatty acid (PUFA) present in large concentrations in the brain and, due to the presence of six double bonds in its structure, is highly susceptible to oxidation by enzymes and reactive oxygen/nitrogen species. The peroxidation of PUFAs has been implicated in an increasing number of human disorders, including neurodegenerative diseases. Hence, a better understanding of the metabolism pathways of DHA should provide new insights about its role in neurodegenerative diseases. Here we review the main aspects related to DHA metabolism, as well as, the recent findings showing its association with neurodegenerative diseases.Keywords: docosahexaenoic acid; metabolism; neurodegenerative diseases. INTRODUÇÃOOs lipídios constituem um grupo heterogêneo de compostos que têm papel crucial na célula, cuja característica comum é a solubilidade em solventes orgânicos e insolubilidade na água. As funções biológicas dos mesmos são tão diversas quanto a sua química. Sua importância pode ser notada pelo número crescente de estudos apontando o envolvimento de seus produtos de oxidação e de disfunções no metabolismo de lipídios em doenças crônico-degenerativas. 1-4Os ácidos graxos são ácidos carboxílicos com cadeias de hidrocarbonetos contendo de 4 a 36 carbonos, sendo encontrados principalmente esterificados a triglicerídios, colesterol e fosfolipídios constituintes das membranas celulares. Eles podem ser classificados em saturados (contendo apenas ligações simples), monoinsaturados (uma ligação dupla) ou poli-insaturados (duas ou mais ligações duplas). Os ácidos graxos poli-insaturados podem ser representados usando-se a abreviação estrutural que os identifica única e exclusivamente através do número de carbonos e de duplas ligações. Também podem ser denominados a partir da posição das ligações duplas, em relação ao grupamento metila terminal, utilizando-se para tanto a denominação ω ou n, 5 sendo a denominação n a recomendada pela IUPAC. 6Estudos mostram que os ácidos graxos poli-insaturados n-3 (ômega-3) e n-6 (ômega-6) têm efeitos distintos nas células, sendo o primeiro associado a efeitos benéficos e o segundo, a efeitos deletérios. 7,8 Os ácidos linoleico (18:2n-6) e linolênico (18:3n-3) são os precursores dos ácidos graxos n-6 e n-3, respectivamente. São considerados essenciais por não serem sintetizados de novo pelos tecidos de vertebrados, sendo necessária a ingestão destes pela dieta. 9O ácido docosahexaenoico (4,7,10,13,16,19-22:6, DHA) é um ácido graxo ômega-3 de 22 carbonos e 6 insaturações. Está enriquecido nas membranas neurais do córtex cerebral e na retina, 10,11 onde 25-35% se encontram esterificados em aminofosfolipídios como a fosfatidilserina, fosfatidiletanolamina e em plasmalogênios.12,13 O DHA constitui > 17% do peso total de ácidos graxos no cérebro de ratos adultos e > 33% do total ...

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Molecular Insights into the Interaction between α-Synuclein and Docosahexaenoic Acid

Cited by 64 publications

References 87 publications

Direct Membrane Association Drives Mitochondrial Fission by the Parkinson Disease-associated Protein α-Synuclein

Direct Membrane Association Drives Mitochondrial Fission by the Parkinson Disease-associated Protein α-Synuclein

Structural and Morphological Characterization of Aggregated Species of α-Synuclein Induced by Docosahexaenoic Acid

Metabolismo, oxidação e implicações biológicas do ácido docosahexaenoico em doenças neurodegenerativas

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