α-Synuclein phosphorylation as a therapeutic target in Parkinson's disease

Steven P. Braithwaite, Jeffry B. Stock, M. Maral Mouradian

Research output: Contribution to journalReview articlepeer-review

35 Scopus citations

Abstract

Phosphorylation is a key post-translational modification necessary for normal cellular signaling and, therefore, lies at the heart of cellular function. In neurodegenerative disorders, abnormal hyperphosphorylation of pathogenic proteins is a common phenomenon that contributes in important ways to the disease process. A prototypical protein that is hyperphosphorylated in the brain is α-synuclein (α-syn) - found in Lewy bodies and Lewy neurites - the pathological hallmarks of Parkinson's disease (PD) and other α-synucleinopathies. The genetic linkage of α-syn to PD as well as its pathological association in both genetic and sporadic cases have made it the primary protein of interest. In understanding how α-syn dysfunction occurs, increasing focus is being placed on its abnormal aggregation and the contribution of phosphorylation to this process. Studies of both the kinases and phosphatases that regulate α-syn phosphorylation are beginning to reveal the roles of this post-translational modification in disease pathogenesis. Modulation of α-syn phosphorylation may ultimately prove to be a viable strategy for disease-modifying therapeutic interventions. In this review, we explore mechanisms related to α-syn phosphorylation, its biophysical and functional consequences, and its role in neurodegeneration.

Original languageEnglish (US)
Pages (from-to)191-198
Number of pages8
JournalReviews in the Neurosciences
Volume23
Issue number2
DOIs
StatePublished - Apr 1 2012

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Keywords

  • GRK
  • LRRK2
  • PLK
  • PP2A
  • aggregation
  • casein kinase

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