Dopamin, oxidativer Stress und Protein‐Chinonmodifikationen bei Parkinson und anderen neurodegenerativen Erkrankungen

Abstract

Dopamin (DA) ist das wichtigste und häufigste Catecholamin im Gehirn und zugleich Vorläufer anderer Neurotransmitter. Die Degeneration von Neuronen des Nigrostriatums (Substantia nigra, Pars compacta) bei Parkinson‐Kranken ist die am besten untersuchte Verknüpfung zwischen Neurotransmission und Neuropathologie durch DA. Catecholamine sind reaktive Moleküle, für die es komplexe Kontroll‐ und Transportsysteme gibt. Unter normalen Bedingungen werden kleine Mengen cytosolischen Dopamins unter Melanisierung von Peptiden und Proteinen schrittweise zu Neuromelanin umgewandelt. Überschießendes cytosolisches oder extraneuronales DA kann allerdings unselektive Proteinmodifikationen auslösen. Die dabei ablaufende Oxidation von DA zu Chinonverbindungen hängt von der Gegenwart redoxaktiver Übergangsmetallionen wie Eisen und Kupfer ab. Auch andere oxidierte DA‐Metaboliten sind wahrscheinlich an posttranslationalen Proteinmodifikationen beteiligt. Die Protein‐Chinonmodifikation ist also ein heterogener Vorgang mit verschiedenen DA‐Abkömmlingen, die Struktur‐ und Konformationsänderungen von Proteinen hervorrufen; dies kann zur Aggregation und Inaktivierung der modifizierten Proteine führen.

Observation and Kinetic Characterization of Transient Schiff Base Intermediates by CEST NMR Spectroscopy

“…We previously showed that the primary, highly toxic dopamine metabolite, 3,4‐dihydroxyphenylacetaldehyde or DOPAL, reacts with lysine sidechain amino groups to form dicatechol pyrrole lysine (DCPL) adducts, that can further react to form covalent intermolecular isoindole linkages . This pathway is at the core of the “catechol‐aldehyde hypothesis”, which provides a plausible link between DOPAL and the presence of α‐synuclein‐containing aggregates in dopaminergic neurons of Parkinson's disease patients . The first step in the reaction pathway of the DCPL adduct formation involves a Schiff base linkage between the DOPAL aldehyde and the Lys ϵ‐amino group .…”

“…This pathway is at the core of the “catechol‐aldehyde hypothesis”, which provides a plausible link between DOPAL and the presence of α‐synuclein‐containing aggregates in dopaminergic neurons of Parkinson's disease patients . The first step in the reaction pathway of the DCPL adduct formation involves a Schiff base linkage between the DOPAL aldehyde and the Lys ϵ‐amino group . Mass spectrometry confirmed the presence of DOPAL Schiff base adducts, but typically involved trapping by cyanoborohydride, and made it difficult to assess their populations and lifetimes under physiological conditions .…”

DOPA pheomelanin is increased in nigral neuromelanin of Parkinson’s disease and it exacerbates alpha-synuclein neurotoxicity

“…Structurally, the casing model of mixed melanogenesis in the periphery (20,21), previously applied to brain NM, has been reformulated based on more recent evidence (22).…”

“…Protein/peptide fibrils constitute the core of NM particles on which quinone molecules produced by oxidative stress react, producing a melanic coat. The initial process resembles pheomelanin formation, as it involves mainly the exposed cysteine thiols of the fibrils, but also histidines and possibly lysines (22). Then, a chain of oxidation/condensation reactions of DA produce oligomers of unstructured eumelanic type (22).…”

“…The initial process resembles pheomelanin formation, as it involves mainly the exposed cysteine thiols of the fibrils, but also histidines and possibly lysines (22). Then, a chain of oxidation/condensation reactions of DA produce oligomers of unstructured eumelanic type (22). This process therefore differs from eumelanin formation in peripheral melanins and explains the lack of the characteristic structural feature of 3.5 Å typical of layers of DA eumelanin oligomers (23).…”