Urate mitigates oxidative stress and motor neuron toxicity of astrocytes derived from ALS-linked SOD1G93A mutant mice

Rachit Bakshi; Yuehang Xu; Kaly A Mueller; Xiqun Chen; Eric Granucci; Sabrina Paganoni; Ghazaleh Sadri-Vakili; Michael A Schwarzschild

doi:10.1016/j.mcn.2018.06.002

Urate mitigates oxidative stress and motor neuron toxicity of astrocytes derived from ALS-linked SOD1^G93A mutant mice

Mol Cell Neurosci. 2018 Oct:92:12-16. doi: 10.1016/j.mcn.2018.06.002. Epub 2018 Jun 18.

Authors

Rachit Bakshi¹, Yuehang Xu², Kaly A Mueller³, Xiqun Chen², Eric Granucci³, Sabrina Paganoni⁴, Ghazaleh Sadri-Vakili³, Michael A Schwarzschild²

Affiliations

¹ Molecular Neurobiology Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, MA, USA. Electronic address: rbakshi1@mgh.harvard.edu.
² Molecular Neurobiology Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, MA, USA.
³ NeuroEpigenetics Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, MA, USA.
⁴ Neurological Clinical Research Institute, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Department of PM&R, Spaulding Rehabilitation Hospital, USA.

PMID: 29928993
DOI: 10.1016/j.mcn.2018.06.002

Abstract

Dominant mutations in an antioxidant enzyme superoxide dismutase-1 (SOD1) cause amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease characterized by loss of motor neurons. Oxidative stress has also been linked to many of the neurodegenerative diseases and is likely a central mechanism of motor neuron death in ALS. Astrocytes derived from mutant SOD1^G93A mouse models or patients play a significant role in the degeneration of spinal motor neurons in ALS through a non-cell-autonomous process. Here we characterize the neuroprotective effects and mechanisms of urate (a.k.a. uric acid), a major endogenous antioxidant and a biomarker of favorable ALS progression rates, in a cellular model of ALS. Our results demonstrate a significant protective effect of urate against motor neuron injury evoked by mutant astrocytes derived from SOD1^G93A mice or hydrogen peroxide induced oxidative stress. Overall, these results implicate astrocyte dependent protective effect of urate in a cellular model of ALS. These findings together with our biomarker data may advance novel targets for treating motor neuron disease.

Keywords: Amyotrophic lateral sclerosis; Oxidative stress; SOD1(G93A) mice; Uric acid.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyotrophic Lateral Sclerosis / genetics
Amyotrophic Lateral Sclerosis / metabolism*
Animals
Antioxidants / pharmacology*
Astrocytes / metabolism*
Cell Line
Cells, Cultured
Culture Media, Conditioned / pharmacology
Mice
Motor Neurons / drug effects
Motor Neurons / metabolism*
Mutation
Oxidative Stress*
Superoxide Dismutase-1 / genetics*
Uric Acid / metabolism
Uric Acid / pharmacology*

Substances

Antioxidants
Culture Media, Conditioned
Uric Acid
Sod1 protein, mouse
Superoxide Dismutase-1