A functionalized hydroxydopamine quinone links thiol modification to neuronal cell death
Ali Farzam1, Karan Chohan2, Miroslava Strmiskova1
1Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie Curie Private, Ottawa, ON, K1N 6N5, Canada.
Redox Biology
|November 25, 2019
Summary
Dopamine oxidation products like 6-hydroxydopamine (6-OHDA) modify proteins, particularly cysteine thiols, impacting cell viability. This study links dopamine oxidation to protein folding dysfunction in Parkinson's disease models.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- Dopamine oxidation is implicated in Parkinson's disease (PD) pathogenesis.
- Mechanisms linking dopamine oxidation to neurodegeneration are not fully understood.
- 6-hydroxydopamine (6-OHDA) is a key dopamine oxidation product used to model PD.
Purpose of the Study:
- To investigate the reactivity of 6-OHDA and its role in protein modification.
- To elucidate the impact of 6-OHDA-induced protein modification on cellular function and viability.
- To explore the connection between dopamine oxidation, protein folding, and PD.
Main Methods:
- Utilized a synthetic alkyne-functionalized 6-OHDA variant.
- Employed Huisgen cycloaddition chemistry (click chemistry) and fluorescence imaging.
- Performed mass spectrometry to identify 6-OHDA modified proteins and in vitro assays.
Main Results:
- Reactive 6-OHDA p-quinones extensively modify proteins, targeting cysteine thiols.
- Identified numerous 6-OHDA modified proteins, including those involved in redox regulation.
- Demonstrated that 6-OHDA inactivates protein disulfide isomerase (PDI), affecting protein folding and redox homeostasis.
Conclusions:
- Dopamine oxidation leads to widespread protein modification in dopaminergic neurons.
- Inactivation of key proteins like PDI by 6-OHDA contributes to cellular dysfunction in PD.
- This study provides mechanistic insights into dopamine oxidation's role in Parkinson's disease.
