Parkin interacting substrate zinc finger protein 746 is a pathological mediator in Parkinson's disease

Saurav Brahmachari, Saebom Lee, Sangjune Kim, Changqing Yuan, Senthilkumar S. Karuppagounder, Preston Ge, Rosa Shi, Esther J. Kim, Alex Liu, Donghoon Kim, Stephan Quintin, Haisong Jiang, Manoj Kumar, Seung Pil Yun, Tae In Kam, Xiaobo Mao, Yunjong Lee, Deborah A. Swing, Lino Tessarollo, Han Seok KoValina L. Dawson, Ted M. Dawson

Research output: Contribution to journalArticle

Abstract

α-Synuclein misfolding and aggregation plays a major role in the pathogenesis of Parkinson's disease. Although loss of function mutations in the ubiquitin ligase, parkin, cause autosomal recessive Parkinson's disease, there is evidence that parkin is inactivated in sporadic Parkinson's disease. Whether parkin inactivation is a driver of neurodegeneration in sporadic Parkinson's disease or a mere spectator is unknown. Here we show that parkin in inactivated through c-Abelson kinase phosphorylation of parkin in three α-synuclein-induced models of neurodegeneration. This results in the accumulation of parkin interacting substrate protein (zinc finger protein 746) and aminoacyl tRNA synthetase complex interacting multifunctional protein 2 with increased parkin interacting substrate protein levels playing a critical role in α-synuclein-induced neurodegeneration, since knockout of parkin interacting substrate protein attenuates the degenerative process. Thus, accumulation of parkin interacting substrate protein links parkin inactivation and α-synuclein in a common pathogenic neurodegenerative pathway relevant to both sporadic and familial forms Parkinson's disease. Thus, suppression of parkin interacting substrate protein could be a potential therapeutic strategy to halt the progression of Parkinson's disease and related α-synucleinopathies.

Original languageEnglish (US)
Pages (from-to)2380-2401
Number of pages22
JournalBrain
Volume142
Issue number8
DOIs
StatePublished - Aug 1 2019

Keywords

  • PARIS
  • Parkinson's disease
  • parkin
  • zinc finger protein 746
  • α-synuclein

ASJC Scopus subject areas

  • Clinical Neurology

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  • Cite this

    Brahmachari, S., Lee, S., Kim, S., Yuan, C., Karuppagounder, S. S., Ge, P., Shi, R., Kim, E. J., Liu, A., Kim, D., Quintin, S., Jiang, H., Kumar, M., Yun, S. P., Kam, T. I., Mao, X., Lee, Y., Swing, D. A., Tessarollo, L., ... Dawson, T. M. (2019). Parkin interacting substrate zinc finger protein 746 is a pathological mediator in Parkinson's disease. Brain, 142(8), 2380-2401. https://doi.org/10.1093/brain/awz172