The concept of “aldehyde load” in neurodegenerative mechanisms: Cytotoxicity of the polyamine degradation products hydrogen peroxide, acrolein, 3-aminopropanal, 3-acetamidopropanal and 4-aminobutanal in a retinal ganglion cell line

Wood, Paul L.; Khan, M. Amin; Moskal, Joseph R.

doi:10.1016/j.brainres.2006.10.004

Cited by 82 publications

(84 citation statements)

References 52 publications

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“…We have recently shown that cells with non-functional NPC1 were more susceptible to the toxic effects of an endogenous lysosomal, membraneimpermeant polyamine metabolite (3-aminopropanal), relative to wild type cells. 3-Aminopropanal has been previously shown to be a potent neurotoxin implicated in neurodegenerative disorders (43)(44)(45)(46). It is thought to cause its toxic effects through its ability to react with and disrupt lysosomal membranes once sequestered in this compartment.…”

Section: Discussionmentioning

confidence: 99%

Niemann-Pick C1 Functions Independently of Niemann-Pick C2 in the Initial Stage of Retrograde Transport of Membrane-impermeable Lysosomal Cargo

Goldman

Krise

2010

Journal of Biological Chemistry

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The rare neurodegenerative disease Niemann-Pick Type C (NPC) results from mutations in either NPC1 or NPC2, which are membrane-bound and soluble lysosomal proteins, respectively. Previous studies have shown that mutations in either protein result in biochemically indistinguishable phenotypes, most notably the hyper-accumulation of cholesterol and other cargo in lysosomes. We comparatively evaluated the kinetics of [ 3 H]dextran release from lysosomes of wild type, NPC1, NPC2, and NPC1/NPC2 pseudo-double mutant cells and found significant differences between all cell types examined. Specifically, NPC1 or NPC2 mutant fibroblasts treated with NPC1 or NPC2 siRNA (to create NPC1/NPC2 pseudo-double mutants) secreted dextran less efficiently than did either NPC1 or NPC2 single mutant cell lines, suggesting that the two proteins may work independently of one another in the egress of membrane-impermeable lysosomal cargo. To investigate the basis for these differences, we examined the role of NPC1 and NPC2 in the retrograde fusion of lysosomes with late endosomes to create so-called hybrid organelles, which is believed to be the initial step in the egress of cargo from lysosomes. We show here that cells with mutated NPC1 have significantly reduced rates of late endosome/lysosome fusion relative to wild type cells, whereas cells with mutations in NPC2 have rates that are similar to those observed in wild type cells. Instead of being involved in hybrid organelle formation, we show that NPC2 is required for efficient membrane fission events from nascent hybrid organelles, which is thought to be required for the reformation of lysosomes and the release of lysosomal cargo-containing membrane vesicles. Collectively, these results suggest that NPC1 and NPC2 can function independently of one another in the egress of certain membrane-impermeable lysosomal cargo.

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Section: Discussionmentioning

confidence: 99%

Niemann-Pick C1 Functions Independently of Niemann-Pick C2 in the Initial Stage of Retrograde Transport of Membrane-impermeable Lysosomal Cargo

Goldman

Krise

2010

Journal of Biological Chemistry

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“…In a very recent review focused on the ACR involvement in neurodisorders [32], the authors pointed out that one of the emerging suspected culprits in their development is ACR, which tends to be significantly elevated in the brains or spinal cords of people who have Alzheimer's disease, PD, amyotrophic lateral sclerosis, and other neurologic disorders [30,[33][34][35][36]. Wood et al [37] developed the concept of ''aldehyde load'' in neurodegenerative mechanisms and underlined the role of polyamine metabolism in generating a number of reactive aldehydes that participate in the death of compromised tissue.…”

Section: Acr Involvement In Diseasesmentioning

confidence: 99%

Protein modification by acrolein: Relevance to pathological conditions and inhibition by aldehyde sequestering agents

Aldini

Orioli

Carini

2011

Molecular Nutrition Food Res

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Acrolein (ACR) is a toxic and highly reactive α,β-unsaturated aldehyde widely distributed in the environment as a common pollutant and generated endogenously mainly by lipoxidation reactions. Its biological effects are due to its ability to react with the nucleophilic sites of proteins, to form covalently modified biomolecules which are thought to be involved as pathogenic factors in the onset and progression of many pathological conditions such as cardiovascular and neurodegenerative diseases. Functional impairment of structural proteins and enzymes by covalent modification (crosslinking) and triggering of key cell signalling systems are now well-recognized signs of cell and tissue damage induced by reactive carbonyl species (RCS). In this review, we mainly focus on the in vitro and in vivo evidence demonstrating the ability of ACR to covalently modify protein structures, in order to gain a deeper insight into the dysregulation of cellular and metabolic pathways caused by such modifications. In addition, by considering RCS and RCS-modified proteins as drug targets, this survey will provide an overview on the newly developed molecules specifically tested for direct or indirect ACR scavenging, and the more significant studies performed in the last years attesting the efficacy of compounds already recognized as promising aldehyde-sequestering agents.

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“…3-AP is formed endogenously from the metabolism of spermidine to putrescine by the enzyme polyamine oxidase. This compound was selected because it has been shown to be specifically toxic to lysosomes through its ability to facilitate membrane rupture, and there have been numerous reports on its neurotoxic effects (48,49). Consistent with the NPC disease pathology, 3-AP has been shown to be particularly toxic to neuronal cells relative to other cells for unknown reasons (50).…”

Section: Npc1 Is Required For the Efficient Clearance Of Amines Trappmentioning

confidence: 99%

Niemann-Pick C1 Functions in Regulating Lysosomal Amine Content

Kaufmann

Krise

2008

Journal of Biological Chemistry

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Mutations in the late endosomal/lysosomal membrane protein Niemann-Pick C1 (NPC1) are known to cause a generalized block in retrograde vesicle-mediated transport, resulting in the hyper-accumulation of multiple lysosomal cargos. An important, yet often overlooked, category of lysosomal cargo includes the vast array of small molecular weight amine-containing molecules that are substrates for ion trapping in the highly acidic organelle lumen. We show here that the introduction of aminecontaining molecules in lysosomes can significantly stimulate NPC1-mediated late endosome/lysosome fusion, and subsequently the secretion of lysosomal cargo. To illustrate the physiological importance of this NPC1-mediated transport pathway, we show that NPC1-deficient cells are more susceptible to the toxic effects of a lysosomotropic polyamine metabolite 3-aminopropanal. Moreover, NPC fibroblasts are shown to have higher levels of polyamine oxidase, an enzyme involved in the formation of 3-aminopropanal. Collectively, these findings provide strong support for a novel functional role for NPC1 and may also provide clues toward understanding NPC disease progression.

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The concept of “aldehyde load” in neurodegenerative mechanisms: Cytotoxicity of the polyamine degradation products hydrogen peroxide, acrolein, 3-aminopropanal, 3-acetamidopropanal and 4-aminobutanal in a retinal ganglion cell line

Cited by 82 publications

References 52 publications

Niemann-Pick C1 Functions Independently of Niemann-Pick C2 in the Initial Stage of Retrograde Transport of Membrane-impermeable Lysosomal Cargo

Niemann-Pick C1 Functions Independently of Niemann-Pick C2 in the Initial Stage of Retrograde Transport of Membrane-impermeable Lysosomal Cargo

Protein modification by acrolein: Relevance to pathological conditions and inhibition by aldehyde sequestering agents

Niemann-Pick C1 Functions in Regulating Lysosomal Amine Content

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