Abstract
Accumulation of aggregated alpha-synuclein (α-syn) is believed to play a pivotal role in the pathophysiology of Parkinson’s disease (PD) and other synucleinopathies. As a key constituent of Lewy pathology, more than 90% of α-syn in Lewy bodies is phosphorylated at serine-129 (pS129) and hence, it is used extensively as a marker for α-syn pathology. However, the exact role of pS129 remains controversial and the kinase(s) responsible for the phosphorylation have yet to be determined. In this study, we investigated the effect of Polo-like kinase 2 (PLK2) inhibition on formation of pS129 using an ex vivo organotypic brain slice model of synucleinopathy. Our data demonstrated that PLK2 inhibition has no effect on α-syn aggregation, pS129 or inter-neuronal spreading of the aggregated α-syn seen in the organotypic slices. Instead, PLK2 inhibition reduced the soluble pS129 level in the nuclei. The same finding was replicated in an in vivo mouse model of templated α-syn aggregation and in human dopaminergic neurons, suggesting that PLK2 is more likely to be involved in S129-phosphorylation of the soluble physiological fraction of α-syn. We also demonstrated that reduction of nuclear pS129 following PLK2 inhibition for a short time before sample collection improves the signal-to-noise ratio when quantifying pS129 aggregate pathology.
Highlights
Mounting evidence from biochemical, pathological and genetic studies strongly suggests a role of alpha-synuclein (α-syn) in the pathogenesis of a group of neurodegenerative diseases, collectively called synucleinopathies [1]
The aggregated α-syn is a main constituent of Lewy pathology detected in neuronal axons and soma in Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), and in oligodendrocytes as glial cytoplasmic inclusions in multiple system atrophy (MSA) [1]. α-Syn is subject to multiple types of posttranslational modifications [2], and phosphorylation at serine-129 has attracted special attention as approximately 90% of aggregated α-syn in the brains of PD patients is stably phosphorylated at this site [3,4,5]
The findings of this study demonstrate that Polo-like kinase 2 (PLK2) is involved in significant S129-phosphorylation of physiological α-syn but not the phosphorylation of serine-129 on aggregated α-syn
Summary
Mounting evidence from biochemical, pathological and genetic studies strongly suggests a role of alpha-synuclein (α-syn) in the pathogenesis of a group of neurodegenerative diseases, collectively called synucleinopathies [1]. These diseases, which include Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), share a common pathological hallmark, namely the development of inclusions containing α-syn aggregates in affected brain cells. Some studies demonstrate an increased toxicity associated with S129-phosphorylation [8, 9, 11], whereas others suggests it has no role in α-syn aggregation or toxicity [12, 13] or even being a protective modification [6, 7]
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