Mutation of the caspase-3 cleavage site in the astroglial glutamate transporter EAAT2 delays disease progression and extends lifespan in the SOD1-G93A mouse model of ALS.

Mutation of the caspase-3 cleavage site in the astroglial glutamate transporter EAAT2 delays disease progression and extends lifespan in the SOD1-G93A mouse model of ALS.
Exp Neurol. 2017 Mar 22;:
Authors: Rosenblum LT, Shamamandri-Markandaiah S, Ghosh B, Foran E, Lepore AC, Pasinelli P, Trotti D
Abstract
Downregulation in the astroglial glutamate transporter EAAT2 in amyotrophic lateral sclerosis (ALS) patients and mutant SOD1 mouse models of ALS is believed to contribute to the death of motor neurons by excitotoxicity. We previously reported that caspase-3 cleaves EAAT2 at a unique cleavage consensus site located in its c-terminus domain, a proteolytic cleavage that also occurs in vivo in the mutant SOD1 mouse model of ALS and leads to accumulation of a sumoylated EAAT2 C-Terminus fragment (CTE-SUMO1) beginning around onset of disease. CTE-SUMO1 accumulates in PML nuclear bodies of astrocytes and causes them to alter their mature phenotypes and secrete factors toxic to motor neurons. Here, we report that mutating the caspase-3 consensus site in the EAAT2 sequence with an aspartate to asparagine mutation (D504N), thereby inhibiting caspase-3 cleavage of EAAT2, confers protection to the SOD1-G93A mouse. EAAT2-D504N knock-in mutant mice were generated and crossed with SOD1-G93A mice to assess the in vivo pathogenic relevance for ALS symptoms of EAAT2 cleavage. The mutation did not affect normal EAAT2 function nor non-ALS mice. In agre...

Source: Experimental Neurology - March 22, 2017 Category: Neurology Authors: Rosenblum LT, Shamamandri-Markandaiah S, Ghosh B, Foran E, Lepore AC, Pasinelli P, Trotti D Tags: Exp Neurol Source Type: research