Neuromelanins in various regions of human brain are associated with native and oxidized isoprenoid lipids

Ward, Weslyn C.; Zucca, Fabio A.; Bellei, Chiara; Zecca, Luigi; Simon, John D.

doi:10.1016/j.abb.2009.01.013

Cited by 14 publications

(15 citation statements)

References 18 publications

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“…Although the elemental analysis suggests that CAL-NM contains a much higher lipid content than the other NMs, the low 2.0/5.1 ppm and 1.6/5.1 ppm intensity ratios indicate a high level of unsaturation; therefore, simple dolichol is likely not the main lipid component. This result is in accordance with previously published results of lipid analysis from the NMs of the various brain areas [28], which showed that the lipid extracts of SN-NM and other-NMs contained ∼25% and ∼10% dolichol/dolichoic acid, respectively, whereas the lipid extract of CAL-NM contained only ∼1% dolichol. While the nature of the main components of CAL-NM lipids has not yet been clarified, it is clear from both the 1 H NMR spectrum and the elemental analysis results that these lipids are highly unsaturated, and possibly oxidized.…”

Section: Resultssupporting

confidence: 93%

Neuromelanins of Human Brain Have Soluble and Insoluble Components with Dolichols Attached to the Melanic Structure

et al. 2012

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Neuromelanins (NMs) are neuronal pigments of melanic-lipidic type which accumulate during aging. They are involved in protective and degenerative mechanisms depending on the cellular context, however their structures are still poorly understood. NMs from nine human brain areas were analyzed in detail. Elemental analysis led to identification of three types of NM, while infrared spectroscopy showed that NMs from neurons of substantia nigra and locus coeruleus, which selectively degenerate in Parkinson’s disease, have similar structure but different from NMs from brain regions not targeted by the disease. Synthetic melanins containing Fe and bovine serum albumin were prepared to model the natural product and help clarifying the structure of NMs. Extensive nuclear magnetic resonance spectroscopy studies showed the presence of dolichols both in the soluble and insoluble parts of NM. Diffusion measurements demonstrated that the dimethyl sulfoxide soluble components consist of oligomeric precursors with MWs in the range 1.4–52 kDa, while the insoluble part contains polymers of larger size but with a similar composition. These data suggest that the selective vulnerability of neurons of substantia nigra and locus coeruleus in Parkinson’s disease might depend on the structure of the pigment. Moreover, they allow to propose a pathway for NM biosynthesis in human brain.

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Section: Resultssupporting

confidence: 93%

Neuromelanins of Human Brain Have Soluble and Insoluble Components with Dolichols Attached to the Melanic Structure

et al. 2012

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“…This role is demonstrated by in vitro studies, where NM significantly reduced basal and iron-stimulated lipid peroxidation in rat cortex (Ben-Shachar et al 1991). NM has indeed been reported to be formed also in pre-motor cortex (Ward et al 2009).…”

Section: Neuromelaninmentioning

confidence: 79%

The relevance of iron in the pathogenesis of Parkinson’s disease

Sian-Hülsmann

Mandel²,

Youdim

et al. 2011

Journal of Neurochemistry

311

214

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J. Neurochem. (2011) 118, 939–957. Abstract Alterations of iron levels in the brain has been observed and documented in a number of neurodegenerative disorders including Parkinson’s disease (PD). The elevated nigral iron levels observed in PD may reflect a dysfunction of brain iron homeostasis. Under normal physiological conditions excess iron can be sequestrated in ferritin and neuromelanin. Alternatively, the excess iron may represent a component of brain iron deposition associated with ageing. The aetiology of idiopathic PD largely remains an enigma. However, intensive investigations have provided a host of putative mechanisms that might contribute to the pathogenesis underlying the characteristic degeneration of the dopaminergic neurons in the substantia nigra (SN). The mechanisms proposed include oxidative (and nitrative) stress, inflammation, excitotoxicity, mitochondrial dysfunction, altered proteolysis and finally apoptotic induced cell death. Iron‐mediated cellular destruction is mediated primarily via reactive oxygen or/and nitrogen species induced oxidative stress. Furthermore, these pathogenic mechanisms appear to be closely interlinked to the cascade of events leading to cellular death. There are conflicting reports about the stage during disease progression at which nigral iron change occurs in PD. Some have found that there are no changes in iron content SN in asymptomatic incidental Lewy body disease, suggesting it may represent a secondary event in the cascade of neuronal degeneration. In contrast, others have found an elevation of iron in SN in pre‐clinical stages. These discrepancies may be attributed to the occurrence of different sub‐groups of the disease. This concurs with the notion that PD represents a group of related diseases with a number of potential pathogenic pathways.

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“…Fedorow et al [47] have shown that dolichol is the major lipid component of neuromelanin derived from the human nervous system and suggests that dolichol may play a protective role mitigating the lipid peroxidation observed in Parkinson's disease. Furthermore, Ward et al [48] have observed oxidation products of dolichols in neurologically normal human autopsy brain tissue. Recently, dolichol-like compounds with a terminal-epoxide structure, resembling brain oxidized dolichols, have been detected in the skipjack tuna liver [49].…”

Section: Discussionmentioning

confidence: 99%

Dolichol: A Component of the Cellular Antioxidant Machinery

Cavallini

Sgarbossa

Parentini

et al. 2016

Lipids

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Dolichol, an end product of the mevalonate pathway, has been proposed as a biomarker of aging, but its biological role, not to mention its catabolism, has not been fully understood. UV-B radiation was used to induce oxidative stress in isolated rat hepatocytes by the collagenase method. Effects on dolichol, phospholipid-bound polyunsaturated fatty acids (PL-PUFA) and known lipid soluble antioxidants [coenzyme Q (CoQ) and α-tocopherol] were studied. The increase in oxidative stress was detected by a probe sensitive to reactive oxygen species (ROS). Peroxidation of lipids was assessed by measuring the release of thiobarbituric acid reactive substances (TBARS). Dolichol, CoQ, and α-tocopherol were assessed by high-pressure liquid chromatography (HPLC), PL-PUFA by gas-liquid chromatography (GC). UV-B radiation caused an immediate increase in ROS as well as lipid peroxidation and a simultaneous decrease in the levels of dolichol and lipid soluble antioxidants. Decrease in dolichol paralleled changes in CoQ levels and was smaller to that in α-tocopherol. The addition of mevinolin, a competitive inhibitor of the enzyme 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoAR), magnified the loss of dolichol and was associated with an increase in TBARS production. Changes in PL-PUFA were minor. These findings highlight that oxidative stress has very early and similar effects on dolichol and lipid soluble antioxidants. Lower levels of dolichol are associated with enhanced peroxidation of lipids, which suggest that dolichol may have a protective role in the antioxidant machinery of cell membranes and perhaps be a key to understanding some adverse effects of statin therapy.

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Neuromelanins in various regions of human brain are associated with native and oxidized isoprenoid lipids

Cited by 14 publications

References 18 publications

Neuromelanins of Human Brain Have Soluble and Insoluble Components with Dolichols Attached to the Melanic Structure

Neuromelanins of Human Brain Have Soluble and Insoluble Components with Dolichols Attached to the Melanic Structure

The relevance of iron in the pathogenesis of Parkinson’s disease

Dolichol: A Component of the Cellular Antioxidant Machinery

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