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 SOD1G93A 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 SOD1G93A 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 SOD1G93A 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 SOD1G93A 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 SOD1G93A 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.

Astrocyte-specific overexpressed gene signatures in response to methamphetamine exposure in vitro

“…Interestingly, astrocytes have been previously suggested as important cellular targets in CNS motor disorders [87, 88], although specific molecular targets are not clear. In the context of Meth abuse, movement disorders are very common sequels and comorbidities [89].…”

Gene expression profiling of the astrocyte transcriptome in multiple sclerosis normal appearing white matter reveals a neuroprotective role

“…An increasing number of studies in a range of neurological diseases have used this approach to identify disease-relevant, cell-specific gene expression changes (Boone et al, 2013, Chu et al, 2009, Kumar et al, 2013, Pietersen et al, 2009, Simpson et al, 2011, Baker et al, 2015. To date, only two studies have employed LCM in the investigation of human MS cases: one identifying gene expression changes in total extracts from NAWM, peri-lesional and lesional regions compared to control WM (Mycko et al, 2012) and the other identifying transcriptomic changes in the vascular compartment in MS (Cunnea et al, 2010); with neither study specifically assessing changes in the astrocyte transcriptome.…”

Cortical Neurotoxic Astrocytes with Early ALS Pathology and miR-146a Deficit Replicate Gliosis Markers of Symptomatic SOD1G93A Mouse Model

“…Astrocytes isolated from cortices at 0-2 day-old mSOD1 mice have previously exhibited enhanced reactivity [61], though those of mSOD1 rodents isolated from the SC of 1day-old pups revealed to express lower levels of S100B and Cx43, and more GLT-1, than those obtained from the adult SC of symptomatic animals [13]. Nevertheless, it was lately shown that astrocytes from the cerebral cortices of 7-8 day-old mice P301S tau transgenic mice possess an abnormal phenotype that is retained in adulthood, in contrast with those from 1 to 2 day-old mice, indicating that the astrocytic reaction can take some days to develop [62].…”