Microcystin-LR Exposure Damages Neurons by Inducing α-Syn Aggregation via MAPK4/GATA2/SNCA and PP2A/GRKs Pathways

Abstract

Microcystin-LR (MC-LR) is a natural neurotoxin with strong toxicity, and studies have demonstrated that chronic MC-LR exposure generated Parkinson-like dyskinesia in mice. Parkinson's disease (PD) is a neurologic degenerative disease mostly occurring in elderly people, and the progressive loss of dopaminergic neurons and the formation of Lewy bodies are the hallmark pathological features. The main component of Lewy bodies is α-synuclein (α-syn) encoded by the SNCA gene, and the copy number mutation of SNCA gene can promote the overexpression of α-syn. A mouse model of MC-LR exposure for 15 months was established to confirm the deposition of Lewy bodies. SH-SY5Y cells exposed to MC-LR were constructed as an in vitro model of PD, and the transcription factor that regulated the SNCA gene (the encoding gene of α-syn) was identified through the database. MC-LR enhanced the transcription level of SNCA gene and upregulated α-syn protein expression by promoting MAPK4 into the nucleus and binding to GATA2 295-480 fragment. In addition, MC-LR inhibited PP2A activity and activated GRKs kinase to promote α-syn phosphorylation at Ser129. These results suggest that MC-LR is involved in α-syn aggregate formation and PD pathogenesis by enhancing SNCA transcriptional activity to promote α-syn elevation via the MAPK4/GATA2 pathway and inducing α-syn phosphorylation via the PP2A/GRKs pathway.

Keywords: GATA2/MAPK4/SNCA pathway; Microcystin-LR; Neuronal apoptosis; PP2A/GRKs pathway; α-Synuclein.