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Resistance of naturally secreted a-synuclein to proteolysis

Resistance of naturally secreted a-synuclein to proteolysis
Resistance of naturally secreted a-synuclein to proteolysis
Recent evidence suggests that specific extracellular ?-synuclein (?-syn) strains are implicated in the progression of Parkinson's disease (PD) pathology. It is plausible that deregulation in the normal processing of secreted ?-syn may be a causative risk factor for PD. To date, the degradation mechanisms involved have received very little attention. Here, we sought to investigate factors that regulate extracellular ?-syn levels. We show, for the first time, that cell-secreted ?-syn forms are resistant to direct proteolysis by kallikrein-related peptidase 6 (KLK6), an extracellular enzyme known to cleave recombinant ?-syn. This differential susceptibility appears to be partially due to the association of secreted ?-syn with lipids. We further provide evidence that secreted ?-syn can be cleaved by KLK6 indirectly through activation of a secreted metalloprotease, suggestive of the involvement of a proteolytic cascade in the catabolism of secreted ?-syn. Our results clearly suggest that physiological modifications affect the biochemical behavior of secreted ?-syn and provide novel insights into mechanisms and potential targets for therapeutic interventions
0892-6638
3146-3158
Ximerakis, Methodios
dea2aa4d-64cb-440e-99f5-d1dcf3dc0395
Pampalakis, Georgios
65c34928-561b-40ab-bc56-e07985554844
Roumeliotis, Theodoros I.
23f78732-120b-407c-97bb-c73022305810
Sykioti, Vasia-Samantha
311eecd8-1a05-45f4-b893-a9813784dd27
Garbis, Spiros D.
7067fd19-50c9-4d42-9611-f370289470bd
Stafanis, Leonidas
1d1db7b8-506a-4e56-8d27-7d44c80ee852
Sotiropoulou, Georgia
190b16e0-e09a-45ef-99ff-53f76be4f513
Vekrellis, Kostas
0d76d598-854b-4dd6-9db1-7603580f4bc2
Ximerakis, Methodios
dea2aa4d-64cb-440e-99f5-d1dcf3dc0395
Pampalakis, Georgios
65c34928-561b-40ab-bc56-e07985554844
Roumeliotis, Theodoros I.
23f78732-120b-407c-97bb-c73022305810
Sykioti, Vasia-Samantha
311eecd8-1a05-45f4-b893-a9813784dd27
Garbis, Spiros D.
7067fd19-50c9-4d42-9611-f370289470bd
Stafanis, Leonidas
1d1db7b8-506a-4e56-8d27-7d44c80ee852
Sotiropoulou, Georgia
190b16e0-e09a-45ef-99ff-53f76be4f513
Vekrellis, Kostas
0d76d598-854b-4dd6-9db1-7603580f4bc2

Ximerakis, Methodios, Pampalakis, Georgios, Roumeliotis, Theodoros I., Sykioti, Vasia-Samantha, Garbis, Spiros D., Stafanis, Leonidas, Sotiropoulou, Georgia and Vekrellis, Kostas (2014) Resistance of naturally secreted a-synuclein to proteolysis. The FASEB Journal, 28 (7), 3146-3158. (doi:10.1096/fj.13-245852). (PMID:24723692)

Record type: Article

Abstract

Recent evidence suggests that specific extracellular ?-synuclein (?-syn) strains are implicated in the progression of Parkinson's disease (PD) pathology. It is plausible that deregulation in the normal processing of secreted ?-syn may be a causative risk factor for PD. To date, the degradation mechanisms involved have received very little attention. Here, we sought to investigate factors that regulate extracellular ?-syn levels. We show, for the first time, that cell-secreted ?-syn forms are resistant to direct proteolysis by kallikrein-related peptidase 6 (KLK6), an extracellular enzyme known to cleave recombinant ?-syn. This differential susceptibility appears to be partially due to the association of secreted ?-syn with lipids. We further provide evidence that secreted ?-syn can be cleaved by KLK6 indirectly through activation of a secreted metalloprotease, suggestive of the involvement of a proteolytic cascade in the catabolism of secreted ?-syn. Our results clearly suggest that physiological modifications affect the biochemical behavior of secreted ?-syn and provide novel insights into mechanisms and potential targets for therapeutic interventions

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More information

e-pub ahead of print date: 10 April 2014
Published date: July 2014
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 395401
URI: http://eprints.soton.ac.uk/id/eprint/395401
ISSN: 0892-6638
PURE UUID: 29121d12-9601-4aa1-a845-034bf49b94df
ORCID for Spiros D. Garbis: ORCID iD orcid.org/0000-0002-1050-0805

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Date deposited: 31 May 2016 08:13
Last modified: 15 Mar 2024 00:39

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Contributors

Author: Methodios Ximerakis
Author: Georgios Pampalakis
Author: Theodoros I. Roumeliotis
Author: Vasia-Samantha Sykioti
Author: Spiros D. Garbis ORCID iD
Author: Leonidas Stafanis
Author: Georgia Sotiropoulou
Author: Kostas Vekrellis

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