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SCIENTIFIC LITERATURE · MED

Are glutathionylated aldehyde reductases the missing piece of the "catecholaldehyde hypothesis" in Parkinson's disease? A medical hypothesis concerning the detoxification of 4-hydroxynonenal (HNE) and 3,4-dihydroxyphenylacetaldehyde (DOPAL).

Rotondo R, Russo M, Iacovelli F, Calabrese V, de Iure A, Gaglione M, Leonardi L, Cocorocchia G, Stocchi F, Stocchi V, de Pandis MF, Picconi B.

Redox Biol · 2026-01-27

DOI: 10.1016/j.redox.2026.104060PMID: 41637878

Open accessResearch Support, Non-U.S. Gov't; research-article; Journal ArticleOriginal source ↗

Research overview

The text below is the source article’s original abstract under a verified reuse license. cc by

The autotoxicity of the monoamine oxidase (MAO) reaction product 3,4-dihydroxyphenylacetaldehyde (DOPAL) is central to the "catecholaldehyde hypothesis", which posits that interactions between DOPAL and the protein α-synuclein contribute to the degeneration of catecholaminergic neurons in Parkinson's disease (PD). Dopamine (DA) can undergo spontaneous or enzymatic oxidation, generating dopamine-quinone (DA-Q) and DOPAL, respectively. While growing evidence highlights the quinonization of numerous proteins in catecholaminergic cells due to the high reactivity of DA-Q, the electrophilic properties of DOPAL and its quinone derivative (DOPAL-quinone, DOPAL-Q) have received less attention, along with potential detoxification pathways. Here, we propose a refinement of the "catecholaldehyde hypothesis" by extending the detoxification machinery described for 3-glutathionyl-4-hydroxynonenal (GS-HNE) to the formation of glutathionylated DOPAL adducts. Conjugation of DOPAL-Q with glutathione (GSH) would generate 5-S-glutathionyl-3,4-dihydroxyphenylacetaldehyde (GS-DOPAL). Analogous to GS-HNE, the aldehyde group of GS-DOPAL could be reduced to 5-S-glutathionyl-3,4-dihydroxyphenylethanol (GS-DOPET) by glutathione-dependent aldehyde reductases such as aldose reductase (AKR1B1) and carbonyl reductase 1 (CBR1). Conversely, oxidation of the phenolic hydroxyl groups by CBR1 to yield 5-S-glutathionyl-3,4-dioxophenylacetaldehyde (GS-DOPAL-Q) may also occur. We suggest that the excretion of such GS-adducts via glutathione-electrophile transporters could open new perspectives for identifying early biomarkers of PD and for evaluating the disease-modifying potential of MAO inhibitors.

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