Abstract
Parkinson’s disease (PD) is the most prevalent movement disorder characterized with loss of dopaminergic neurons in the brain. One of the pathological hallmarks of the disease is accumulation of aggregated α-synuclein (αSyn) in cytoplasmic Lewy body inclusions that indicates significant dysfunction of protein homeostasis in PD. Accumulation is accompanied with highly elevated S129 phosphorylation, suggesting that this posttranslational modification is linked to pathogenicity and altered αSyn inclusion dynamics. To address the role of S129 phosphorylation on protein dynamics further we investigated the wild type and S129A variants using yeast and a tandem fluorescent timer protein reporter approach to monitor protein turnover and stability. Overexpression of both variants leads to inhibited yeast growth. Soluble S129A is more stable and additional Y133F substitution permits αSyn degradation in a phosphorylation-independent manner. Quantitative cellular proteomics revealed significant αSyn-dependent disturbances of the cellular protein homeostasis, which are increased upon S129 phosphorylation. Disturbances are characterized by decreased abundance of the ubiquitin-dependent protein degradation machinery. Biotin proximity labelling revealed that αSyn interacts with the Rpt2 base subunit. Proteasome subunit depletion by reducing the expression of the corresponding genes enhances αSyn toxicity. Our studies demonstrate that turnover of αSyn and depletion of the proteasome pool correlate in a complex relationship between altered proteasome composition and increased αSyn toxicity.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting about 1% of the population older than 60 years
The proteotoxicity of αSyn is dependent on its turnover, which is influenced by various posttranslational modifications
Overexpression of αSyn, as well as the S129A or Y133F variants that are deficient in phosphorylation or nitration, significantly inhibits yeast growth (Figure 1A). αSyn is abundantly phosphorylated at serine 129 and can be phosphorylated or nitrated at tyrosine 133
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting about 1% of the population older than 60 years. A major constituent of Lewy bodies is the protein alpha-synuclein (αSyn) [3]. Human αSyn is a pre-synaptic protein, containing 140 amino acids, and is abundantly expressed in the brain. Missense mutations in αSyn alleles have been identified in rare familial inherited forms of PD [7,8,9,10,11]. Duplication and triplication of αSyn genes leading to overexpression of the gene product represent alternative genetic causes for PD [12,13]. These results suggest that an increase in the αSyn protein expression level could be sufficient to cause neurodegenerative disease
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
