Skip to main content
Journal cover image

Age-associated insolubility of parkin in human midbrain is linked to redox balance and sequestration of reactive dopamine metabolites.

Publication ,  Journal Article
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 ...
Published in: Acta Neuropathol
May 2021

The mechanisms by which parkin protects the adult human brain from Parkinson disease remain incompletely understood. We hypothesized that parkin cysteines participate in redox reactions and that these are reflected in its posttranslational modifications. We found that in post mortem human brain, including in the Substantia nigra, parkin is largely insoluble after age 40 years; this transition is linked to its oxidation, such as at residues Cys95 and Cys253. In mice, oxidative stress induces posttranslational modifications of parkin cysteines that lower its solubility in vivo. Similarly, oxidation of recombinant parkin by hydrogen peroxide (H2O2) promotes its insolubility and aggregate formation, and in exchange leads to the reduction of H2O2. This thiol-based redox activity is diminished by parkin point mutants, e.g., p.C431F and p.G328E. In prkn-null mice, H2O2 levels are increased under oxidative stress conditions, such as acutely by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxin exposure or chronically due to a second, genetic hit; H2O2 levels are also significantly increased in parkin-deficient human brain. In dopamine toxicity studies, wild-type parkin, but not disease-linked mutants, protects human dopaminergic cells, in part through lowering H2O2. Parkin also neutralizes reactive, electrophilic dopamine metabolites via adduct formation, which occurs foremost at the primate-specific residue Cys95. Further, wild-type but not p.C95A-mutant parkin augments melanin formation in vitro. By probing sections of adult, human midbrain from control individuals with epitope-mapped, monoclonal antibodies, we found specific and robust parkin reactivity that co-localizes with neuromelanin pigment, frequently within LAMP-3/CD63+ lysosomes. We conclude that oxidative modifications of parkin cysteines are associated with protective outcomes, which include the reduction of H2O2, conjugation of reactive dopamine metabolites, sequestration of radicals within insoluble aggregates, and increased melanin formation. The loss of these complementary redox effects may augment oxidative stress during ageing in dopamine-producing cells of mutant PRKN allele carriers, thereby enhancing the risk of Parkinson's-linked neurodegeneration.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Acta Neuropathol

DOI

EISSN

1432-0533

Publication Date

May 2021

Volume

141

Issue

5

Start / End Page

725 / 754

Location

Germany

Related Subject Headings

  • Young Adult
  • Ubiquitin-Protein Ligases
  • Oxidation-Reduction
  • Neurology & Neurosurgery
  • Nerve Degeneration
  • Middle Aged
  • Mice, Inbred C57BL
  • Mice
  • Mesencephalon
  • Male
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Tokarew, J. M., El-Kodsi, D. N., Lengacher, N. A., Fehr, T. K., Nguyen, A. P., Shutinoski, B., … Schlossmacher, M. G. (2021). Age-associated insolubility of parkin in human midbrain is linked to redox balance and sequestration of reactive dopamine metabolites. Acta Neuropathol, 141(5), 725–754. https://doi.org/10.1007/s00401-021-02285-4
Tokarew, Jacqueline M., Daniel N. El-Kodsi, Nathalie A. Lengacher, Travis K. Fehr, Angela P. Nguyen, Bojan Shutinoski, Brian O’Nuallain, et al. “Age-associated insolubility of parkin in human midbrain is linked to redox balance and sequestration of reactive dopamine metabolites.Acta Neuropathol 141, no. 5 (May 2021): 725–54. https://doi.org/10.1007/s00401-021-02285-4.
Tokarew JM, El-Kodsi DN, Lengacher NA, Fehr TK, Nguyen AP, Shutinoski B, et al. 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):725–54.
Tokarew, Jacqueline M., et al. “Age-associated insolubility of parkin in human midbrain is linked to redox balance and sequestration of reactive dopamine metabolites.Acta Neuropathol, vol. 141, no. 5, May 2021, pp. 725–54. Pubmed, doi:10.1007/s00401-021-02285-4.
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):725–754.
Journal cover image

Published In

Acta Neuropathol

DOI

EISSN

1432-0533

Publication Date

May 2021

Volume

141

Issue

5

Start / End Page

725 / 754

Location

Germany

Related Subject Headings

  • Young Adult
  • Ubiquitin-Protein Ligases
  • Oxidation-Reduction
  • Neurology & Neurosurgery
  • Nerve Degeneration
  • Middle Aged
  • Mice, Inbred C57BL
  • Mice
  • Mesencephalon
  • Male