Faculty Collaboration Database

SMN deficiency does not induce oxidative stress in SMA iPSC-derived astrocytes or motor neurons. Hum Mol Genet 2016 Feb 01;25(3):514-23

Date

12/09/2015

Pubmed ID

26643950

DOI

10.1093/hmg/ddv489

Scopus ID

2-s2.0-84960888922 (requires institutional sign-in at Scopus site)   30 Citations

Abstract

Spinal muscular atrophy (SMA) is a genetic disorder characterized by loss of motor neurons in the spinal cord leading to muscle atrophy and death. Although motor neurons (MNs) are the most obviously affected cells in SMA, recent evidence suggest dysfunction in multiple cell types. Astrocytes are a crucial component of the motor circuit and are intimately involved with MN health and maintenance. We have previously shown that SMA astrocytes are altered both morphologically and functionally early in disease progression, though it is unclear what causes astrocytes to become reactive. Oxidative stress is a common feature among neurodegenerative diseases. Oxidative stress can both induce apoptosis in neurons and can cause astrocytes to become reactive, which are features observed in the SMA induced pluripotent stem cell (iPSC) cultures. Therefore, we asked if oxidative stress contributes to SMA astrocyte pathology. We examined mitochondrial bioenergetics, transcript and protein levels of oxidative and anti-oxidant factors, and reactive oxygen species (ROS) production and found little evidence of oxidative stress. We did observe a significant increase in endogenous catalase expression in SMA iPSCs. While catalase knockdown in SMA iPSCs increased ROS production above basal levels, levels of ROS remained lower than in controls, further arguing against robust oxidative stress in this system. Viral delivery of survival motor neuron (SMN) reversed astrocyte activation and restored catalase levels to normal, without changing mitochondrial respiration or expression of oxidative stress markers. Taken together, these data indicate that SMN deficiency induces astrocyte reactivity, but does not do so through an oxidative stress-mediated process.

Author List

Patitucci TN, Ebert AD

Authors

Allison D. Ebert PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Teresa Patitucci PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Astrocytes
Catalase
Cell Differentiation
Gene Expression Regulation
Glutamate-Cysteine Ligase
Glutathione Peroxidase
Humans
Induced Pluripotent Stem Cells
Mitochondria
Motor Neurons
Muscular Atrophy, Spinal
NAD(P)H Dehydrogenase (Quinone)
NF-E2-Related Factor 2
Neural Stem Cells
Oxidative Phosphorylation
Oxidative Stress
Primary Cell Culture
RNA, Small Interfering
Reactive Oxygen Species
Spinal Cord
Superoxide Dismutase