Neuroprotective effect of CuATSM on neurotoxin-induced motor neuron loss in an ALS mouse model

Michael T H Kuo; Joseph S Beckman; Christopher A Shaw

doi:10.1016/j.nbd.2019.104495

Neuroprotective effect of CuATSM on neurotoxin-induced motor neuron loss in an ALS mouse model

Neurobiol Dis. 2019 Oct:130:104495. doi: 10.1016/j.nbd.2019.104495. Epub 2019 Jun 7.

Authors

Michael T H Kuo¹, Joseph S Beckman², Christopher A Shaw³

Affiliations

¹ Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: michael.kuo@ubc.ca.
² Linus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR, United States.
³ Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, British Columbia, Canada; Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada; Program in Neuroscience, University of British Columbia, Vancouver, British Columbia, Canada; Program in Experimental Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

PMID: 31181282
DOI: 10.1016/j.nbd.2019.104495

Abstract

CuATSM is a PET-imaging agent that has recently received attention for its success in extending the lifespan in animals in several neurodegenerative disease models. In the SOD1^G93A model of ALS, CuATSM prolonged mouse longevity far longer than any previously tested therapeutic agents. The mechanism underlying this outcome has not been fully understood, but studies suggest that this copper complex contributes to maintaining copper homeostasis in mitochondria. More specifically for the SOD1 model, the molecule supplies copper back to the SOD1 protein. Additionally, CuATSM demonstrated similar protective effects in various in vivo Parkinson's disease mouse models. In the current pilot study, we utilized a neurodegenerative mouse model of motor neuron degeneration induced by the neurotoxin β-sitosterol β-D-glucoside. In this model, slow but distinct and progressive features of sporadic ALS occur. Treatment with CuATSM kept animal behavioural performance on par with the controls and prevented the extensive motor neuron degeneration and microglia activation seen in the untreated animals. These outcomes support a broader neuroprotective role for CuATSM beyond mutant SOD models of ALS.

Keywords: ALS; Amyotrophic lateral sclerosis; Copper homeostasis; CuATSM; Neurodegeneration; Therapeutics.

Publication types

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

MeSH terms

Amyotrophic Lateral Sclerosis / pathology*
Animals
Copper / pharmacology*
Disease Models, Animal
Mice
Motor Neurons / drug effects*
Motor Neurons / pathology*
Nerve Degeneration / pathology
Neuroprotective Agents / pharmacology*
Neurotoxins / toxicity

Substances

Neuroprotective Agents
Neurotoxins
Copper