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Interplay between sumoylation and phosphorylation for protection against α-synuclein inclusions
Hedieh Shahpasandzadeh1, Blagovesta Popova1, Alexandra Kleinknecht1
1From the Institute of Microbiology and Genetics, Department of Molecular Microbiology and Genetics, Georg-August-Universität Göttingen, D-37077 Göttingen, Germany, the Center for Nanoscale Microscopy and Molecular Physiology of the Brain, D-37073 Göttingen, Germany.
The Journal of Biological Chemistry
|September 19, 2014
Summary
Sumoylation of alpha-synuclein protects against Parkinson disease pathology by aiding aggregate clearance. Phosphorylation can compensate for sumoylation defects, promoting clearance via autophagy and proteasomal pathways.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Parkinson disease involves dopaminergic neuron loss and Lewy body formation, primarily of alpha-synuclein.
- Alpha-synuclein undergoes post-translational modifications like phosphorylation and sumoylation, crucial for its function and aggregation.
- The interplay between alpha-synuclein sumoylation and phosphorylation in Parkinson disease pathogenesis remains unclear.
Purpose of the Study:
- To investigate the interplay between alpha-synuclein sumoylation and phosphorylation.
- To determine the impact of these modifications on cell growth and inclusion formation in a yeast model.
- To explore potential therapeutic strategies targeting these modifications for Parkinson disease.
Main Methods:
- Utilized a yeast model to study alpha-synuclein modifications in vivo.
- Assessed the effects of impaired sumoylation and phosphorylation on yeast growth and inclusion formation.
- Investigated the roles of autophagy and proteasomal degradation in aggregate clearance.
Main Results:
- Alpha-synuclein sumoylation occurs at conserved sites in yeast, similar to human cells.
- Impaired sumoylation led to reduced yeast growth and increased alpha-synuclein inclusions, indicating a protective role for sumoylation.
- Inhibition of sumoylation blocked autophagy-mediated aggregate clearance.
- Serine 129 phosphorylation by GRK5 suppressed sumoylation defects, reduced inclusions, and promoted aggregate clearance via both autophagy and proteasomal pathways.
Conclusions:
- Sumoylation plays a protective role in preventing alpha-synuclein aggregation and promoting its clearance.
- Phosphorylation can counteract the negative effects of sumoylation deficiency, facilitating aggregate clearance.
- The findings highlight a complex interplay between sumoylation and phosphorylation in alpha-synuclein aggregate clearance, offering potential therapeutic targets for Parkinson disease.
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