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Publications of the Week

Neuroprotective Effect of CuATSM on Neurotoxin-Induced Motor Neuron Loss in an ALS Mouse Model

By July 5, 2019No Comments

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This week we profile a recent publication in Neubiology of Disease from the laboratory of Dr. Chris Shaw (pictured) at UBC.

Can you provide a brief overview of your lab’s current research focus?

Our current focus is on amyotrophic lateral sclerosis (ALS), also called Lou Gehrig’s disease, a neurodegenerative disease with an estimated annual mortality of 30,000 worldwide. Life expectancy of ALS patients from symptom onset is, on average, two to five years. The disease causes a progressive loss of motor neurons, leading to a deterioration of motor function and eventually manifests with respiratory failure leading to death. ALS cases can be broadly categorized into two forms: familial ALS (fALS), 5 to 10% of all cases, arising from genetic mutations; sporadic ALS (sALS), the remaining 90% of ALS cases, has no clearly identified cause, but may arise from environmental factors.

Our laboratory specifically focuses on developing and characterizing sALS and forms of Parkinson’s disease (PD) using rodent animal models. Most currently available ALS models are the result of the extensive studies of the genetic mutations found in fALS, and typically focus on the mutations singly. While these genetic models have proven useful in studying disease pathology, progression, and underlying mechanisms, they represent only a small fraction of cases. A model developed in our laboratory differs in that it uses a possible environmental trigger: β-sitosterol-β-d-glucoside (BSSG), a steryl glucoside neurotoxin found in the plant Cycas micronesica. Cycad seed consumption was previously linked to an extremely high incidence of ALS on the island of Guam. Our previous work isolated BSSG and identified it to be one of the most toxic substances found in cycad seeds.

Mice fed with BSSG demonstrate distinct ALS–like features that worsen over time in behavioural assessments and show a significant decrease in large motor neurons along with increased activity in microglia, the nervous system’s innate inflammatory cells that are involved in neurodegeneration.

These model features allow us a working framework in which to test potential therapeutics for ALS.

What is the significance of the findings in this publication?

CuATSM, a copper homeostasis regulating compound, has been used as a PET-imaging agent for hypoxic tumours in humans. Recent studies have shown that the application of this molecule remarkably extends the lifespan of mice with mutant superoxide dismutase 1 mutations (mSOD1), one of the major ALS genetic models. CuATSM used in this model system by our collaborators has shown a remarkable level of motor neuron preservation. We have now expanded these previous studies and have reported that CuATSM applied in our BSSG model at the same time prevents most of the deleterious aspects of BSSG alone.

The combined data support a role for CuATSM as a potential therapeutic for ALS. These data also highlight the likely importance of mitochondria in neurological diseases.

What are the next steps for this research?

While our current study has shown the possibility that CuATSM can prevent the onset of ALS in mice, the next crucial goal would be to demonstrate that it can also halt the underlying disease process once it has already begun. To do so will require that we apply BSSG until a certain level of motor neuron loss has occurred, then determine if CuATSM can prevent the progression of the disorder. If so, such results would make the compound potentially of great therapeutic benefit in ALS patients.

If you’d like us to mention your funding sources, please list them.

This study is supported by a grant from a generous donation by the Luther Allyn Shourds Dean Estate.

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