Helper cells in the brain, which support nerve function, change their behaviour with the progression of Motor Neuron Disease (MND), a new study has found.
Researchers at the Sheffield Institute for Translational Neuroscience (SITraN) discovered the star-shaped cells, called astrocytes, progressively lose the ability to support motor neurons as MND progresses leading to the death of the specialised nerve cells that control our movements.
The pioneering study revealed the full extent of astrocyte behaviour in a mouse model of MND from pre-symptomatic to late stages of the disease.
Co-lead of the study, Dr. Janine Kirby, Senior Lecturer in Neurogenetics at the University of Sheffield, said: “Overall, our data suggest that astrocytes react to disease by engaging damage limitation strategies including clearing debris and waste from the motor neurons and redistributing components such as cholesterol, which is crucial for nerve cell function.
“However, as the disease progresses, astrocytes lose their supportive functions and the ability to control their external environment which ultimately leads to the death of the motor neurons.”
Astrocytes are key players in the progression of MND and other neurodegenerative diseases such as Alzheimer’s disease. They have many important supportive functions and are critical for the proper functioning and survival of nerve cells.
In order to provide the first detailed map of astrocyte behaviour throughout the disease course, researcher and study co-author Dr David Baker investigated differences in gene expression in astrocytes in a well-characterised mouse model of MND which carries the SOD1G93A mutation. The team confirmed their findings with further enzymatic essays and in vitro experiments.
One of the senior researchers of this study, Marie Curie Research Fellow Dr Laura Ferraiuolo, and the team at SITraN have previously shown that astrocytes at the pre-symptomatic stage are known to lose some supportive functions to motor neurons seen in the decreased provision of growth factors as well as lactate needed to generate energy.
The new data shows that as the disease progresses and symptoms occur, SOD1 astrocytes transition into an activated state.
The reactive astrocytes show an altered stress and immune response compared to their healthy counterparts.
Waste processing and recycling is increased through the activation of lysosomal and phagocytic pathways, most likely to protect nerve cells from the accumulation of cell debris which can cause inflammation and lead to cell death (apoptosis).
The late stage shows additional changes in cholesterol production and distribution which is also critical for neuron survival.
Clinician Scientist in Neurology and MND specialist Professor Dame Pam Shaw, Director of SITraN and co-lead of this study, said: “Taken together, SOD1G93A astrocytes are characterized by a loss of supportive function towards motor neurons, as well as acquiring toxic properties during the disease course, and these factors in the neighbourhood of motor neurons compromise the health and survival of the nerve cells.
“The next step will be to determine whether astrocyte behaviour can be modulated or even restored, and whether this is a means by which to slow down disease progression in MND.”
The project was carried out in collaboration with DPZ (the German Primate Center) and the University of Veracruz in Mexico.
Source: Amy Pullan – University of Sheffield Image Source: The image is adapted from the University of Sheffield press release Original Research: Full open access research for “Lysosomal and phagocytic activity is increased in astrocytes during disease progression in the SOD1 G93A mouse model of amyotrophic lateral sclerosis” by Baker, DJ; Blackburn, DJ; Keatinge, M; Sokhi, D; Viskaitis, P; Heath, PR; Ferraiuolo, L; Kirby, J and Shaw, PJ in Frontiers in Cellular Neuroscience. Published online October 16 2015 doi:10.3389/fncel.2015.00410
Lysosomal and phagocytic activity is increased in astrocytes during disease progression in the SOD1 G93A mouse model of amyotrophic lateral sclerosis
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.
“Lysosomal and phagocytic activity is increased in astrocytes during disease progression in the SOD1 G93A mouse model of amyotrophic lateral sclerosis” by Baker, DJ; Blackburn, DJ; Keatinge, M; Sokhi, D; Viskaitis, P; Heath, PR; Ferraiuolo, L; Kirby, J and Shaw, PJ in Frontiers in Cellular Neuroscience. Published online October 16 2015 doi:10.3389/fncel.2015.00410