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Review
. 2022 Oct 17;35(10):1789-1804.
doi: 10.1021/acs.chemrestox.2c00193. Epub 2022 Aug 22.

Role of Protein Damage Inflicted by Dopamine Metabolites in Parkinson's Disease: Evidence, Tools, and Outlook

Alexander K Hurben  1 , Natalia Y Tretyakova  1
Affiliations
Review

Role of Protein Damage Inflicted by Dopamine Metabolites in Parkinson's Disease: Evidence, Tools, and Outlook

Alexander K Hurben et al. Chem Res Toxicol. .

Abstract

Dopamine is an important neurotransmitter that plays a critical role in motivational salience and motor coordination. However, dysregulated dopamine metabolism can result in the formation of reactive electrophilic metabolites which generate covalent adducts with proteins. Such protein damage can impair native protein function and lead to neurotoxicity, ultimately contributing to Parkinson's disease etiology. In this Review, the role of dopamine-induced protein damage in Parkinson's disease is discussed, highlighting the novel chemical tools utilized to drive this effort forward. Continued innovation of methodologies which enable detection, quantification, and functional response elucidation of dopamine-derived protein adducts is critical for advancing this field. Work in this area improves foundational knowledge of the molecular mechanisms that contribute to dopamine-mediated Parkinson's disease progression, potentially assisting with future development of therapeutic interventions.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Loss of dopaminergic neurons in Parkinson’s disease. Pictural representation of autopsied midbrain sections from healthy and PD diagnosed individuals (right and left respectively). Impairment and death of dopaminergic neurons is a hallmark of PD.
Figure 2.
Figure 2.
Primary pathways for dopamine biosynthesis and metabolism. DA is generated from L-Tyr by TH and AADC. DA can be converted by DβH to NE or broken down by two major and minor pathways consisting of transformations catalyzed by MAO, ADH, ALDH, AR and COMT.
Figure 3.
Figure 3.
Dopamine handling systems in neurons. DA is created by TH and AADC which is then sequestered into synaptic vesicles by VMAT2. Excess cytosolic DA is converted to HVA by MAO, ADH, and COMT or enveloped into neuromelanin. Residual DA in the synaptic cleft following release by the presynaptic neuron undergoes reuptake by DAT and is repackaged in synaptic vesicles or is broken down by neighboring astrocytes.
Figure 4.
Figure 4.
Dopamine derived reactive metabolites. A) Oxidation products of DA. DA can undergo a 1 e- oxidation to DASQ or a 2 e- oxidation to DAQ. DAQ cyclizes to LDAC or reacts with ROS to form 6-OHDA. 6-OHDA can further oxidize to 6-OHDQ. LDAC can oxidize to DAC which can rearrange to DHI. DHI can oxidize to DHIQ which polymerizes due to instability. B) Oxidization of DOPAL to DPQAL.
Figure 5.
Figure 5.
Chemical reactions of dopamine metabolites. A) Reactions by DASQ; radical cross coupling, thiol oxidation, superoxide generation, and disproportionation. Shown from top to bottom. B) Reactions by DAQ: intramolecular cyclization, thiol addition, amine addition (shown from top to bottom). Note that other DA-derived quinones can undergo similar additions. C) Reactions by DOPAL; imine condensation, oxidation to DPQAL, and protein crosslink formation to due to nucleophile addition into the ring.
Figure 6.
Figure 6.
Protein damage inflicted by reactive DA metabolites can drive neurotoxicity through enzymatic inhibition and conformational changes.
Figure 7.
Figure 7.
Classes and structures of dopamine mimetic probes.
Figure 8.
Figure 8.
Methods to detect dopamine-protein adducts. Top: Schematic of NBT redox cycle with a DA protein adduct to yield NBF, enabling visualization of DA protein adducts. Bottom: Depiction of the nIRF properties of ortho quinones which enable the detection of DA protein adducts.
Figure 9.
Figure 9.
Technologies to capture dopamine protein adducts. Top: Schematic of boronate functionalized resin utilized to immobilize and release proteins containing a DA adduct. Bottom: Visualization of DA decorated nanoparticles enabling detection of proteins susceptible to DA modification.
Figure 10.
Figure 10.
Identification of dopamine modified proteins by mass spectrometry. Low abundant DA protein adducts are enriched via various strategies (e.g. bioorthogonal chemistry and boronate affinity). This enriched set of proteins is digested to peptides and subjected to LC-MS/MS analysis. The MS spectra can then be searched against a database to enable protein identification.
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