TY  - JOUR
IS  - 50
PB  - National Academy of Sciences
Y1  - 2017/12/12/
A1  - Rott, R
A1  - Szargel, R
A1  - Shani, V
A1  - Hamza, H
A1  - Savyon, M
A1  - Abd Elghani, F
A1  - Bandopadhyay, R
A1  - Engelender, S
SP  - 13176
UR  - https://doi.org/10.1073/pnas.1704351114
KW  - Parkinson?s disease
KW  -  ?-synuclein
KW  -  SUMOylatio
KW  -  nubiquitination
KW  -  aggregation
TI  - SUMOylation and ubiquitination reciprocally regulate ?-synuclein degradation and pathological aggregation
N2  - ?-Synuclein accumulation is a pathological hallmark of Parkinson?s disease (PD). Ubiquitinated ?-synuclein is targeted to proteasomal or lysosomal degradation. Here, we identify SUMOylation as a major mechanism that counteracts ubiquitination by different E3 ubiquitin ligases and regulates ?-synuclein degradation. We report that PIAS2 promotes SUMOylation of ?-synuclein, leading to a decrease in ?-synuclein ubiquitination by SIAH and Nedd4 ubiquitin ligases, and causing its accumulation and aggregation into inclusions. This was associated with an increase in ?-synuclein release from the cells. A SUMO E1 inhibitor, ginkgolic acid, decreases ?-synuclein levels by relieving the inhibition exerted on ?-synuclein proteasomal degradation. ?-Synuclein disease mutants are more SUMOylated compared with the wild-type protein, and this is associated with increased aggregation and inclusion formation. We detected a marked increase in PIAS2 expression along with SUMOylated ?-synuclein in PD brains, providing a causal mechanism underlying the up-regulation of ?-synuclein SUMOylation in the disease. We also found a significant proportion of Lewy bodies in nigral neurons containing SUMO1 and PIAS2. Our observations suggest that SUMOylation of ?-synuclein by PIAS2 promotes ?-synuclein aggregation by two mutually reinforcing mechanisms. First, it has a direct proaggregatory effect on ?-synuclein. Second, SUMOylation facilitates ?-synuclein aggregation by blocking its ubiquitin-dependent degradation pathways and promoting its accumulation. Therefore, inhibitors of ?-synuclein SUMOylation provide a strategy to reduce ?-synuclein levels and possibly aggregation in PD.
VL  - 114
N1  - This version is the author accepted manuscript. For information on re-use, please refer to the publisher?s terms and conditions.
SN  - 0027-8424
ID  - discovery10032511
AV  - public
JF  - Proceedings of the National Academy of Sciences of the United States of America
EP  - 13181
ER  -