Unknown

Dataset Information

0

Lysosomal and phagocytic activity is increased in astrocytes during disease progression in the SOD1 (G93A) mouse model of amyotrophic lateral sclerosis.


ABSTRACT: Astrocytes are key players in the progression of amyotrophic lateral sclerosis (ALS). Previously, gene expression profiling of astrocytes from the pre-symptomatic stage of the SOD1(G93A) model of ALS has revealed reduced lactate metabolism and altered trophic support. Here, we have performed microarray analysis of symptomatic and late-stage disease astrocytes isolated by laser capture microdissection (LCM) from the lumbar spinal cord of the SOD1(G93A) mouse to complete the picture of astrocyte behavior throughout the disease course. Astrocytes at symptomatic and late-stage disease show a distinct up-regulation of transcripts defining a reactive phenotype, such as those involved in the lysosome and phagocytic pathways. Functional analysis of hexosaminidase B enzyme activity in the spinal cord and of astrocyte phagocytic ability has demonstrated a significant increase in lysosomal enzyme activity and phagocytic activity in SOD1(G93A) vs. littermate controls, validating the findings of the microarray study. In addition to the increased reactivity seen at both stages, astrocytes from late-stage disease showed decreased expression of many transcripts involved in cholesterol homeostasis. Staining for the master regulator of cholesterol synthesis, SREBP2, has revealed an increased localization to the cytoplasm of astrocytes and motor neurons in late-stage SOD1(G93A) spinal cord, indicating that down-regulation of transcripts may be due to an excess of cholesterol in the CNS during late-stage disease possibly due to phagocytosis of neuronal debris. Our data reveal that SOD1(G93A) astrocytes are characterized more by a loss of supportive function than a toxic phenotype during ALS disease progression and future studies should focus upon restorative therapies.

SUBMITTER: Baker DJ 

PROVIDER: S-EPMC4606544 | BioStudies | 2015-01-01

REPOSITORIES: biostudies

Similar Datasets

2015-01-01 | S-EPMC4653659 | BioStudies
2012-01-01 | S-EPMC3409288 | BioStudies
2016-01-01 | S-EPMC5063282 | BioStudies
2015-11-02 | E-GEOD-69166 | ArrayExpress
2019-01-01 | S-EPMC6691112 | BioStudies
1000-01-01 | S-EPMC3077460 | BioStudies
2008-01-01 | S-EPMC2656686 | BioStudies
1000-01-01 | S-EPMC3631166 | BioStudies
2012-01-01 | S-EPMC3423406 | BioStudies
2011-01-01 | S-EPMC3207668 | BioStudies