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Review
. 2022 Jun 1;23(11):6216.
doi: 10.3390/ijms23116216.

Pathogenic Impact of α-Synuclein Phosphorylation and Its Kinases in α-Synucleinopathies

Ichiro Kawahata  1 , David I Finkelstein  2 , Kohji Fukunaga  1   3
Affiliations
Review

Pathogenic Impact of α-Synuclein Phosphorylation and Its Kinases in α-Synucleinopathies

Ichiro Kawahata et al. Int J Mol Sci. .

Abstract

α-Synuclein is a protein with a molecular weight of 14.5 kDa and consists of 140 amino acids encoded by the SNCA gene. Missense mutations and gene duplications in the SNCA gene cause hereditary Parkinson's disease. Highly phosphorylated and abnormally aggregated α-synuclein is a major component of Lewy bodies found in neuronal cells of patients with sporadic Parkinson's disease, dementia with Lewy bodies, and glial cytoplasmic inclusion bodies in oligodendrocytes with multiple system atrophy. Aggregated α-synuclein is cytotoxic and plays a central role in the pathogenesis of the above-mentioned synucleinopathies. In a healthy brain, most α-synuclein is unphosphorylated; however, more than 90% of abnormally aggregated α-synuclein in Lewy bodies of patients with Parkinson's disease is phosphorylated at Ser129, which is presumed to be of pathological significance. Several kinases catalyze Ser129 phosphorylation, but the role of phosphorylation enzymes in disease pathogenesis and their relationship to cellular toxicity from phosphorylation are not fully understood in α-synucleinopathy. Consequently, this review focuses on the pathogenic impact of α-synuclein phosphorylation and its kinases during the neurodegeneration process in α-synucleinopathy.

Keywords: Parkinson’s disease; dementia with Lewy bodies; multiple system atrophy; phosphorylation; α-synuclein; α-synucleinopathy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structure and summary of post-translational modification sites of α-synuclein. The schematic represents α-synuclein protein [28] with the N-terminal amphipathic region, non-amyloid component region, and C-terminal acidic region. Phosphorylation sites are indicated in red letters, and ubiquitination is shown in purple. The indicated Ser129 phosphorylation site is the potential region mostly associated with α-synuclein-induced neurodegeneration.
Figure 2
Figure 2
α-Synuclein Ser129 phosphorylation in cultured dopaminergic neurons. Exposure to exogenous α-synuclein fibrils induces the formation of phosphorylated α-synuclein-positive intracellular aggregates. Cells were exposed to ATTO550-labeled α-synuclein fibrils for 48 h. Scale bar = 10 μm, and 1 μm in magnified images of ROI i, ii, and iii. Images were originally obtained for this review.
Figure 3
Figure 3
Summary of representative phosphorylation sites, kinases, and mutation sites of α-synuclein [54,55,56,57,58,59,60,61,62,63,64]. GRK: G-protein-coupled receptor kinase; CKII: casein kinase II; PLK: polo-like kinase; LRRK2: leucine-rich repeat kinase 2; NAC: non-amyloid component.
Figure 4
Figure 4
Schematic pathways of α-synuclein phosphorylation by kinases in the neurodegeneration process and potential pharmacotherapeutic targets [56,104,106,107,108,109,110]. NO: nitric oxide; NOS: NO synthase; ROS: reactive oxygen species; L-NNA: N(omega)-nitro-L-arginine, a competitive inhibitor of nitric oxide synthase; GRK: G-protein-coupled receptor kinase; CKII: casein kinase II; PLK: polo-like kinase; PPX: pramipexole.
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Grants and funding

This research was funded in part by the Japan Society for the Promotion of Science, KAKENHI (19K07097 and 22K06644), Takeda Science Foundation to I.K., Australian National Health and Medical Research Council, The Michael J. Fox Foundation for Parkinson’s Disease Research for D.F., and the Strategic Research Program for Brain Sciences from Japan Agency for Medical Research and Development, AMED (JP21dm0107071) to K.F.