Abstract
Mutations in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS). Accumulating evidence implicates astrocytes as important non‐cell autonomous contributors to ALS pathogenesis, although the potential deleterious effects of astrocytes on the function of motor neurons remains to be determined in a completely humanized model of C9orf72‐mediated ALS. Here, we use a human iPSC‐based model to study the cell autonomous and non‐autonomous consequences of mutant C9orf72 expression by astrocytes. We show that mutant astrocytes both recapitulate key aspects of C9orf72‐related ALS pathology and, upon co‐culture, cause motor neurons to undergo a progressive loss of action potential output due to decreases in the magnitude of voltage‐activated Na+ and K+ currents. Importantly, CRISPR/Cas‐9 mediated excision of the C9orf72 repeat expansion reverses these phenotypes, confirming that the C9orf72 mutation is responsible for both cell‐autonomous astrocyte pathology and non‐cell autonomous motor neuron pathophysiology.
Highlights
Amyotrophic lateral sclerosis (ALS) is characterized by loss of motor neurons (MNs), accumulating experimental and pathological evidence reveal the involvement of other cell types that are implicated in non-cell autonomous toxic effects on MN health (Boillee, Vande Velde, & Cleveland, 2006; Ilieva, Polymenidou, & Cleveland, 2009)
We report chromosome 9 open reading frame 72 (C9orf72)-dependent cell autonomous astrocyte pathology and astrocyte mediated loss of MN function independent of overt effects on MN viability
We show that expression of the C9orf72 mutation in astrocytes recapitulates key aspects of C9orf72-related amyotrophic lateral sclerosis (ALS) pathology and directly results in physiological dysfunction of control and C9orf72
Summary
Amyotrophic lateral sclerosis (ALS) is characterized by loss of motor neurons (MNs), accumulating experimental and pathological evidence reveal the involvement of other cell types that are implicated in non-cell autonomous toxic effects on MN health (Boillee, Vande Velde, & Cleveland, 2006; Ilieva, Polymenidou, & Cleveland, 2009). Studies of MN dysfunction in ALS have primarily focused on cell autonomous mechanisms, whereas a recent study has shown that changes in the physiological properties of MNs can be mediated by ALS-affected mouse astrocytes (Fritz et al, 2013). Together, these studies highlight the need to better understand the nature and functional consequences of astrocyte pathology in ALS. We suggest possible molecular pathways, highlighted from RNA-Seq data, which may underlie loss of MN function
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