eprintid: 10032511
rev_number: 32
eprint_status: archive
userid: 608
dir: disk0/10/03/25/11
datestamp: 2017-11-09 14:51:13
lastmod: 2021-09-25 23:06:06
status_changed: 2017-11-09 14:51:13
type: article
metadata_visibility: show
creators_name: Rott, R
creators_name: Szargel, R
creators_name: Shani, V
creators_name: Hamza, H
creators_name: Savyon, M
creators_name: Abd Elghani, F
creators_name: Bandopadhyay, R
creators_name: Engelender, S
title: SUMOylation and ubiquitination reciprocally regulate α-synuclein degradation and pathological aggregation
ispublished: pub
divisions: UCL
divisions: B02
divisions: C07
divisions: D07
divisions: F84
keywords: Parkinson’s disease, α-synuclein, SUMOylatio, nubiquitination, aggregation
note: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
abstract: α-Synuclein accumulation is a pathological hallmark of Parkinson’s disease (PD). Ubiquitinated α-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 α-synuclein degradation. We report that PIAS2 promotes SUMOylation of α-synuclein, leading to a decrease in α-synuclein ubiquitination by SIAH and Nedd4 ubiquitin ligases, and causing its accumulation and aggregation into inclusions. This was associated with an increase in α-synuclein release from the cells. A SUMO E1 inhibitor, ginkgolic acid, decreases α-synuclein levels by relieving the inhibition exerted on α-synuclein proteasomal degradation. α-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 α-synuclein in PD brains, providing a causal mechanism underlying the up-regulation of α-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 α-synuclein by PIAS2 promotes α-synuclein aggregation by two mutually reinforcing mechanisms. First, it has a direct proaggregatory effect on α-synuclein. Second, SUMOylation facilitates α-synuclein aggregation by blocking its ubiquitin-dependent degradation pathways and promoting its accumulation. Therefore, inhibitors of α-synuclein SUMOylation provide a strategy to reduce α-synuclein levels and possibly aggregation in PD.
date: 2017-12-12
date_type: published
publisher: National Academy of Sciences
official_url: https://doi.org/10.1073/pnas.1704351114
oa_status: green
full_text_type: other
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1506570
doi: 10.1073/pnas.1704351114
lyricists_name: Bandopadhyay, Rina
lyricists_id: RBAND40
actors_name: Dewerpe, Marie
actors_id: MDDEW97
actors_role: owner
full_text_status: public
publication: Proceedings of the National Academy of Sciences of the United States of America
volume: 114
number: 50
pagerange: 13176-13181
issn: 0027-8424
citation:        Rott, R;    Szargel, R;    Shani, V;    Hamza, H;    Savyon, M;    Abd Elghani, F;    Bandopadhyay, R;           Rott, R;  Szargel, R;  Shani, V;  Hamza, H;  Savyon, M;  Abd Elghani, F;  Bandopadhyay, R;  Engelender, S;   - view fewer <#>    (2017)    SUMOylation and ubiquitination reciprocally regulate α-synuclein degradation and pathological aggregation.                   Proceedings of the National Academy of Sciences of the United States of America , 114  (50)   pp. 13176-13181.    10.1073/pnas.1704351114 <https://doi.org/10.1073/pnas.1704351114>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10032511/1/Bandopadhyay_Rott%20PNAS%20oct%2030%2017.pdf