Alpha-synuclein, lipids and Parkinson’s disease

Ruipérez, Violeta; Darios, Frédéric; Davletov, Bazbek

doi:10.1016/j.plipres.2010.05.004

Cited by 200 publications

(173 citation statements)

References 137 publications

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“…These brain regions are largely involved in learning and motor control. Evidence of the involvement of a-synuclein in neurodegeneration came from studies showing that three independent mutations in this synaptic protein lead to the development of familial PD (175). Additional studies demonstrated that duplications and triplications of the a-synuclein gene also cause an early onset of PD (96).…”

Section: Parkinson Diseasementioning

confidence: 99%

“…In particular, markers of lipid peroxidation have been found to be elevated in brain tissues and body fluids in several neurodegenerative diseases, and the role of lipid peroxidation has been widely investigated in the pathogenesis of Alzheimer disease (AD), Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), Huntington disease (HD), and Down syndrome (DS) (32,111,175,176,185).…”

Section: Introductionmentioning

confidence: 99%

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4-Hydroxy-2-Nonenal, a Reactive Product of Lipid Peroxidation, and Neurodegenerative Diseases: A Toxic Combination Illuminated by Redox Proteomics Studies

Perluigi

Coccia

Butterfield

2012

Antioxidants & Redox Signaling

190

133

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Significance: Among different forms of oxidative stress, lipid peroxidation comprises the interaction of free radicals with polyunsaturated fatty acids, which in turn leads to the formation of highly reactive electrophilic aldehydes. Among these, the most abundant aldehydes are 4-hydroxy-2-nonenal (HNE) and malondialdehyde, while acrolein is the most reactive. HNE is considered a robust marker of oxidative stress and a toxic compound for several cell types. Proteins are particularly susceptible to modification caused by HNE, and adduct formation plays a critical role in multiple cellular processes. Recent Advances: With the outstanding progress of proteomics, the identification of putative biomarkers for neurodegenerative disorders has been the main focus of several studies and will continue to be a difficult task. Critical Issues: The present review focuses on the role of lipid peroxidation, particularly of HNE-induced protein modification, in neurodegenerative diseases. By comparing results obtained in different neurodegenerative diseases, it may be possible to identify both similarities and specific differences in addition to better characterize selective neurodegenerative phenomena associated with protein dysfunction. Results obtained in our laboratory and others support the common deregulation of energy metabolism and mitochondrial function in neurodegeneration. Future Directions: Research towards a better understanding of the molecular mechanisms involved in neurodegeneration together with identification of specific targets of oxidative damage is urgently required. Redox proteomics will contribute to broaden the knowledge in regard to potential biomarkers for disease diagnosis and may also provide insight into damaged metabolic networks and potential targets for modulation of disease progression. Antioxid. Redox Signal. 17, 1590-1609.

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Section: Parkinson Diseasementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

4-Hydroxy-2-Nonenal, a Reactive Product of Lipid Peroxidation, and Neurodegenerative Diseases: A Toxic Combination Illuminated by Redox Proteomics Studies

Perluigi

Coccia

Butterfield

2012

Antioxidants & Redox Signaling

190

133

View full text Add to dashboard Cite

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“…Substantial evidence correlates the protein with neuronal membranes (7-9) and brain lipids (10). It has been demonstrated that ␣-syn binds to abundant cerebral polyunsaturated fatty acids (PUFA), such as arachidonic and docosahexaenoic acids (DHA).…”

mentioning

confidence: 99%

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

Franceschi

Frare

Pivato

et al. 2011

Journal of Biological Chemistry

104

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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“…In these cases, symptoms develop in younger ages. dopaminergic neurons that will give rise to eosinophilic cytoplasmic inclusions known as Lewy's bodies [17]. The protein -synuclein is a small lipophilic molecule present at high levels in CNS.…”

Section: Risk Level Environmental Agentmentioning

confidence: 99%

“…In CNS, if ubiquitination and consequent -synuclein degradation do not occur, lead to storage of this protein over time [17]. This fact explains the higher prevalence of the disease in elderly populations.…”

Section: Risk Level Environmental Agentmentioning

confidence: 99%

Genes involved in the development of Parkinson

Teixeira¹,

Cardoso²

2017

Open J Parkinsons Dis Treatm

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Background: Parkinson's disease is the second most important neurodegenerative disorder, affecting 3% of individuals older than 80 years of age. Main clinical symptoms are resting tremor, postural instability, bradykinesia and rigidity, with a good response to levodopa therapy. Purpose of the study:The main goal of this work is to make a deep analysis on the genetic factors and kind of heritage involved in the development of Parkinson. Main fi ndings:Over the last years, numerous studies allowed to confirm the unquestionable contribution of genetic factors to the complex pathogenesis of this disease. Highly penetrant mutations producing rare, monogenic forms of the disease have been identifi ed in singular genes such as SNCA, Parkin, DJ-1, PINK1, LRRK2, and VPS35. Unique variants with incomplete penetrance in LRRK2 and GBA genes were identifi ed as strong risk factors for Parkinson's disease in certain populations. Additionally, over 20 common variants with small effect sizes are now recognized to modulate the risk for Parkinson's disease.Investigating Mendelian forms of Parkinson disease has provided precious insight into the pathophysiology that underlies the more common idiopathic form of this disorder. Conclusions:The challenge over the next decade will be to get more data that strengthens the already available knowledge concerning genetics on Parkinson's disease, through the discovery of biological consequences of risk variants. Moreover, it is also expected that the advent of genome-wide association studies and the implementation of new research technologies will help in the identifi cation of novel risk variants for the sporadic forms of Parkinson disease.

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Alpha-synuclein, lipids and Parkinson’s disease

Cited by 200 publications

References 137 publications

4-Hydroxy-2-Nonenal, a Reactive Product of Lipid Peroxidation, and Neurodegenerative Diseases: A Toxic Combination Illuminated by Redox Proteomics Studies

4-Hydroxy-2-Nonenal, a Reactive Product of Lipid Peroxidation, and Neurodegenerative Diseases: A Toxic Combination Illuminated by Redox Proteomics Studies

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

Genes involved in the development of Parkinson

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