Jacqueline Marie Tokarew | University of Ottawa
Tokarew JM, El-Kodsi DN, Lengacher NA, Fehr TK, Nguyen AP, Shutinoski B, O’Nuallain B, Jin M, Khan JM, Ng ACH, Li J, Jiang Q, Zhang M, Wang L, Sengupta R, Barber KR, Tran A, Im DS, Callaghan S, Park DS, Zandee S, Dong X, Scherzer CR, Prat A, Tsai EC, Takanashi M, Hattori N, Chan JA, Zecca L, West AB, Holmgren A, Puente L, Shaw GS, Toth G, Woulfe JM, Taylor P, Tomlinson JJ, Schlossmacher MG. Age-associated insolubility of parkin in human midbrain is linked to redox balance and sequestration of reactive dopamine metabolites. Acta Neuropathol. 2021 May;141(5)
Parkinson’s disease: Age-associated changes in parkin in the human brain is associated with protective outcomes
The mechanisms by which the parkin protein protects the adult human brain from Parkinson disease remain incompletely understood. Mutations in the gene PRKN, which encodes this protein, lead to a young-onset, recessive form of Parkinson disease (PD). These mutations lead to a loss of neurons in two brain regions that synthesize dopamine, the Substantia nigra and the Locus coeruleus. A new study led by PhD student Jacqueline Marie Tokarew, working in Michael Schlossmacher’s laboratory at the University of Ottawa, investigated the role of parkin in human brains in protecting against Parkinson’s disease and found a novel role for parkin as an antioxidant and regulator of the redox state of cells.
The biochemistry of parkin in the human brain was largely unexplored, and the researchers found that parkin solubility declined with age, and that this effect was unique to human brains and not seen in mice, rats or monkeys. Furthermore, the researchers found this decline in parkin solubility correlated with an increase in hydrogen peroxide levels in the brain, and showed that hydrogen peroxide modified parkin, resulting in a structural change making the protein insoluble, and in exchange, consuming hydrogen peroxide to control its level.
Through an extensive series of experiments, the researchers showed that this process also occurred in human and mouse brains, that hydrogen peroxide levels were increased in parkin deficient brains, and that parkin acted to protect the brain from the damaging effects of excessive amounts of hydrogen peroxide.
This is the first study of its kind to explain several unique aspects of parkin metabolism in the human brain and it challenged the current parkin dogma by demonstrating that oxidative modifications of parkin is not detrimental, but associated with protective outcomes. Of clinical importance, the findings presented here also demonstrated a potential, human-specific link between parkin and neuromelanin formation, which deserves to be further explored, as this substance is unique to human and primate brain.
This discovery helps explain the heretofore poorly understood mechanism causing PRKN-linked Parkinson disease (PD). The researchers propose that the loss of these complementary redox effects augment oxidative stress during ageing in dopamine-producing cells of patients with mutant PRK, thereby enhancing the risk of Parkinson Disease (PD)-linked neurodegeneration.
Future studies focusing on the effect of parkin oxidative modifications on protein structure will provide insight into how they alter parkin function in vivo and contribute to PD pathogenesis. Furthermore, these findings in human brain support the use of pharmacological and toxicological induction of oxidative and dopamine metabolite stress in parkin deficient animals as representative PD research models. Finally, designing clinical trials using antioxidants specifically in individuals affected by PRKN-associated PD (in addition to targeted gene therapy with PRKN cDNA) represents an important treatment approach to explore.
Jacqueline Marie Tokarew
PhD student Jacqueline Marie Tokarew performed this study in Michael Schlossmacher’s laboratory at the University of Ottawa. As co-first author, the applicant provided major contributions to establishing: experimental techniques, the project’s design, data analyses and interpretation, and the initial drafts and edits of this publication.