Astrocytes in neurological disease progression: good intentions gone wrong?

Astrocytes are star-shaped cells that perform important functions in the central nervous system both during homeostasis and upon injury. In reaction to harmful stimuli, astrocytes change their shape, migrate towards the damaged area, and/or secrete repair-stimulating substances. This phenomenon, termed ‘astrocyte reactivity’, is an evolutionary conserved response to limit acute damage to the brain and spinal cord. Nevertheless, in chronic neurological diseases, such as amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS), reactive astrocytes may exacerbate neurological injury. In this thesis, we examined different aspects of astrocyte reactivity in ALS and MS. Small heat-shock proteins (HSPBs) facilitate astrocyte migration and promote astrocyte survival during stress. We demonstrated that rapidly progressive ALS is associated with higher levels of HSPB5 and 8 in astrocytes. We also found that astrocytes in the spinal cord produce more HSPB1, 6, and 8 than astrocytes in the brain, even in individuals without neurological disease. Additionally, we investigated a harmful product of reactive astrocytes: ‘fibronectin aggregates’. We demonstrated that fibronectin aggregates can be cleaved by matrix metalloproteinase 7 (MMP7), while MMP7 is absent from chronic MS lesions. However, lack of MMP7 in an experimental model did not lead to accumulation of remyelination-impairing fibronectin aggregates. The work presented in this dissertation contributes to our knowledge of reactive astrocytes and their harmful products in the brain and spinal cord. Better understanding whether and how the “good intentions” of reactive astrocytes influence the progression of neurological diseases may ultimately lead to new astrocyte-targeting therapies for people with MS and ALS.