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

Author(s): Braithwaite, Steven P; Stock, Jeffry B; Mouradian, M Maral

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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.
Publication Date: 21-Mar-2012
DOI: doi:10.1515/revneuro-2011-0067
ISSN: 0334-1763
EISSN: 2191-0200
Keywords: aggregation, casein kinase, GRK, LRRK2, PLK, PP2A
Type of Material: Journal Article
Journal/Proceeding Title: Reviews in the Neurosciences
Version: Final published version. This is an open access article.

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