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Microcystin-LR Exposure Damages Neurons by Inducing α-Syn Aggregation via MAPK4/GATA2/SNCA and PP2A/GRKs Pathways
Minghao Yan1,2, Huifang Wu1,2, Tong Wu1,2
1State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-Embryology, Medical School, Nanjing University, Nanjing, 210093, Jiangsu, China.
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.
Insights
Microcystin-LR (MC-LR), a neurotoxin, promotes Parkinson
Area of Science:
- Neuroscience
- Toxicology
- Molecular Biology
Background:
- Parkinson's disease (PD) is characterized by dopaminergic neuron loss and Lewy bodies, primarily composed of alpha-synuclein (α-syn).
- SNCA gene copy number mutations can lead to α-syn overexpression, a factor in PD pathogenesis.
- Chronic exposure to the neurotoxin Microcystin-LR (MC-LR) has been linked to Parkinson-like symptoms in mice.
Purpose of the Study:
- To investigate the molecular mechanisms by which MC-LR contributes to Parkinson's disease pathogenesis.
- To establish and characterize in vivo and in vitro models for studying MC-LR's effects on α-synuclein.
- To identify specific pathways involved in MC-LR-induced α-synuclein alterations.
Main Methods:
- Established a 15-month mouse model of chronic MC-LR exposure to assess Lewy body deposition.
- Developed an in vitro SH-SY5Y cell model of PD exposed to MC-LR.
- Utilized database analysis to identify transcription factors regulating the SNCA gene and employed molecular assays to confirm pathway interactions.
Main Results:
- MC-LR exposure led to Lewy body deposition in the mouse model.
- MC-LR upregulated SNCA gene transcription and α-syn protein expression via the MAPK4/GATA2 pathway.
- MC-LR inhibited PP2A activity and activated GRKs, promoting α-syn phosphorylation at Ser129.
Conclusions:
- MC-LR exposure promotes α-synuclein (α-syn) elevation and aggregation, contributing to Parkinson's disease pathogenesis.
- The MAPK4/GATA2 pathway mediates MC-LR-induced enhancement of SNCA transcription and subsequent α-syn upregulation.
- The PP2A/GRKs pathway is involved in MC-LR-induced α-syn phosphorylation, further implicating MC-LR in PD pathology.
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