Astrocytes carrying the superoxide dismutase 1 (SOD1 ^G93A ) mutation induce wild-type motor neuron degeneration in vivo

Abstract

Recent studies highlight astrocytes as key drivers of motor neuron (MN) degeneration and disease propagation in mutant human superoxide dismutase 1 (mSOD1)-mediated amyotrophic lateral sclerosis. However, in vivo analysis of specific astrocytic influence in amyotrophic lateral sclerosis has proven difficult because mSOD1 is ubiquitously expressed throughout the CNS of rodent models studied. Here, we transplanted SOD1 G93A glial-restricted precursor cells-glial progenitors capable of differentiating into astrocytesinto the cervical spinal cord of WT rats to reveal how mutant astrocytes influence WT MNs and other cells types (microglia and astrocytes) in an in vivo setting. Transplanted SOD1G93A glial-restricted precursor cells survived and differentiated efficiently into astrocytes. Graft-derived SOD1G93A astrocytes induced host MN ubiquitination and death, forelimb motor and respiratory dysfunction, reactive astrocytosis, and reduced GLT-1 transporter expression in WT animals. The SOD1 G93A astrocyte-induced MN death seemed in part mediated by host microglial activation. These findings show that mSOD1 astrocytes alone can induce WT MN death and associated pathological changes in vivo.neurodegeneration | stem cells | toxicity A myotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease affecting ≈30,000 individuals in the United States, is characterized by motor neuron (MN) loss leading to paralysis and eventually death (1). Although most ALS cases are sporadic, 5-10% are inherited, with 20% of those cases linked to dominant mutations in the gene encoding for Cu/Zn superoxide dismutase 1 (SOD1) (2). Transgenic rodents engineered to carry mutant human SOD1 (mSOD1) genes broadly recapitulate the human disease (3, 4).Despite the relative selectivity of MN loss in ALS, studies in mSOD1 rodent and tissue culture models implicate nonneuronal (glial) cell types in the disease process (5, 6). Astrocytes in particular are hypothesized to play a role in both mSOD1 and sporadic forms of ALS (5-8). Recently, coculture studies showed selective degeneration of embryonic stem cell-derived MNs by mSOD1-expressing astrocytes, possibly via toxic astrocyte-secreted factors acting through a variety of proposed mechanisms (9-12). These studies shed light on mSOD1 astrocyte-specific influences on MN degeneration independent of mSOD1 expression in MNs. However, it is unknown whether these astrocyte-specific toxicities translate in vivo.Here, glial-restricted precursors (GRPs)-lineage-restricted astrocyte precursors derived from the developing spinal cord (13, 14)-were transplanted into rodent spinal cord to determine whether mSOD1 astrocyte-mediated toxicity to MNs translates in vivo. Specifically, GRPs harboring the human G93A mutation (SOD1 G93A ) were transplanted into the cervical spinal cord ventral horn of WT rats to assess the basic biology of mSOD1 glial lineages in vivo and to address whether SOD1 G93A GRP-derived astrocytes can induce WT MN death or dysfunction in this setting. Findings show that SOD1 G93A a...

Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis

“…Mutant SOD1 expression in astrocytes causes these cells to produce and secrete toxic factors that kill motor neurons (54,62,63). Transplanting astrocytes that express mutant SOD1 in wild-type animals causes motor neuron death (64). Recent evidence also supports an important role of astrocytes in TDP-43-mediated motor neuron toxicity.…”

Are astrocytes executive cells within the central nervous system?

“…Later, other authors also claimed that proteins such as TDP-43, Tau, α-synuclein and SOD1 could acquire prion properties when mutated 54,55,56 .…”

Astrocyte signaling and neurodegeneration

“…131,133 Furthermore, transplantation of mutant SOD1-expressing glial progenitors, capable of differentiating into astrocytes, into the spinal cord of wild-type rats induced motor neuron degeneration and disease symptoms in vivo, definitively confirming a causative role for these cells in ALS. 134 A peculiar histopathological abnormality in tissues of ALS patients is the presence of ubiquitin inclusions within astrocytes. 135 Noteworthy, similar features are shared by mutant SOD1 mice, which show protein aggregates made of SOD1, ubiquitin and/or activated caspase-3 in astroglial cells.…”