Phenotypically aberrant astrocytes that promote motoneuron damage in a model of inherited amyotrophic lateral sclerosis

Abstract

Motoneuron loss and reactive astrocytosis are pathological hallmarks of amyotrophic lateral sclerosis (ALS), a paralytic neurodegenerative disease that can be triggered by mutations in Cu-Zn superoxide dismutase (SOD1). Dysfunctional astrocytes contribute to ALS pathogenesis, inducing motoneuron damage and accelerating disease progression. However, it is unknown whether ALS progression is associated with the appearance of a specific astrocytic phenotype with neurotoxic potential. Here, we report the isolation of astrocytes with aberrant phenotype (referred as “AbA cells”) from primary spinal cord cultures of symptomatic rats expressing the SOD1 G93A mutation. Isolation was based on AbA cells’ marked proliferative capacity and lack of replicative senescence, which allowed oligoclonal cell expansion for 1 y. AbA cells displayed astrocytic markers including glial fibrillary acidic protein, S100β protein, glutamine synthase, and connexin 43 but lacked glutamate transporter 1 and the glial progenitor marker NG2 glycoprotein. Notably, AbA cells secreted soluble factors that induced motoneuron death with a 10-fold higher potency than neonatal SOD1 G93A astrocytes. AbA-like aberrant astrocytes expressing S100β and connexin 43 but lacking NG2 were identified in nearby motoneurons, and their number increased sharply after disease onset. Thus, AbA cells appear to be an as-yet unknown astrocyte population arising during ALS progression with unprecedented proliferative and neurotoxic capacity and may be potential cellular targets for slowing ALS progression.

Evidence for mast cells contributing to neuromuscular pathology in an inherited model of ALS

“…This result is significant, considering that in this animal model, a fulminant paralysis develops in rats aged 5-6 months, rapidly progressing from abnormal gait to complete loss of motor function in a period of 2-3 weeks (27). The therapeutic effect of masitinib in ALS rats was associated with the inhibition of CSF-1R in microglia and aberrant glial cells that surround degenerating spinal motor neurons (33,34). Because masitinib is a multifaceted drug affecting multiple immune cell types, we hypothesized that the protective effect of masitinib in ALS likely involves other inflammatory cell types such as mast cells and macrophages in addition to glial cells.…”

Sigma-1R Agonist Improves Motor Function and Motoneuron Survival in ALS Mice

“…It has been extensively reported that glial cells contribute to MN degeneration, both in animal models [33][34][35] and in ALS patients [36]. Thus, we analyzed both The results showed that PRE-084 administration significantly reduced microglial, but not astroglial immunoreactivity in the ventral horn of SOD1 animals (Figs.…”

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

“…Resveratrol Administration Reduces Microglial Immunoreactivity in the SOD1 G93A Mice Spinal Cord It has been extensively reported that glial cells contribute to MN degeneration both in ALS patients [39] and animal models [40][41][42]. We evaluated astroglial (GFAP labeled cells) and microglial (Iba-1 labeled cells) immunoreactivity in the anterior horns of lumbar spinal cord sections in order to assess whether resveratrol treatment influenced the response of glial cells.…”