Caspase-3 cleaves and inactivates the glutamate transporter EAAT2.

Authors

• William Boston-Howes
• Stuart L Gibb
• Eric O Williams
• Piera Pasinelli
• Robert H Brown
• Davide Trotti

Publication/Presentation Date

5-19-2006

Abstract

EAAT2 is a high affinity, Na+-dependent glutamate transporter with predominant astroglial localization. It accounts for the clearance of the bulk of glutamate released at central nervous system synapses and therefore has a crucial role in shaping glutamatergic neurotransmission and limiting excitotoxicity. Caspase-3 activation and impairment in expression and activity of EAAT2 are two distinct molecular mechanisms occurring in human amyotrophic lateral sclerosis (ALS) and in the transgenic rodent model of the disease. Excitotoxicity caused by down-regulation of EAAT2 is thought to be a contributing factor to motor neuron death in ALS. In this study, we report the novel evidence that caspase-3 cleaves EAAT2 at a unique site located in the cytosolic C-terminal domain of the transporter, a finding that links excitotoxicity and activation of caspase-3 as converging mechanisms in the pathogenesis of ALS. Caspase-3 cleavage of EAAT2 leads to a drastic and selective inhibition of this transporter. Heterologous expression of mutant SOD1 proteins linked to the familial form of ALS leads to inhibition of EAAT2 through a mechanism that largely involves activation of caspase-3 and cleavage of the transporter. In addition, we found evidence in spinal cord homogenates of mutant SOD1 ALS mice of a truncated form of EAAT2, likely deriving from caspase-3-mediated proteolytic cleavage, which appeared concurrently to the loss of EAAT2 immunoreactivity and to increased expression of activated caspase-3. Taken together, our findings suggest that caspase-3 cleavage of EAAT2 is one mechanism responsible for the impairment of glutamate uptake in mutant SOD1-linked ALS.

Volume

281

Issue

20

First Page

14076

Last Page

14084

ISSN

0021-9258

Published In/Presented At

Boston-Howes, W., Gibb, S. L., Williams, E. O., Pasinelli, P., Brown, R. H., Jr, & Trotti, D. (2006). Caspase-3 cleaves and inactivates the glutamate transporter EAAT2. The Journal of biological chemistry, 281(20), 14076–14084. https://doi.org/10.1074/jbc.M600653200

Disciplines

Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods

PubMedID

16567804

Department(s)

Administration and Leadership

Document Type

Article