Rita Sattler, associate professor of neurobiology at Barrow Neurological Institute, Dignity Health – St. Joseph’s Hospital in Phoenix, was awarded an MDA research grant totaling $300,000 over three years to elucidate the mechanisms underlying ALS (amyotrophic lateral sclerosis) caused by expansions in the C9ORF72 gene.
Please describe your current research.
The goal is to study the molecular mechanisms of the newly discovered C9ORF72 gene expansion, which is found in 20-40 percent of familial ALS and 10-20 percent of frontotemporal dementia (FTD) patients. Recent findings suggest that the mutation in C9ORF72, which is characterized by a so-called “repeat expansion” of nucleotides in the DNA, leads to dysfunction of overall cellular RNA processing. Cellular RNA processing is critical as it affects the proper making of the corresponding protein. Therefore, alterations in RNA processing can alter the expression and translation of numerous genes, leading to mislocalized and dysfunctional proteins. In cells in the central nervous system, such as neurons or glial cells, these dysfunctional proteins can be found in the cell body, as well as in cellular processes (axons and dendrites), and affect important cell function.
Preliminary data from our laboratory suggests that there is a structural rearrangement of the synapse, a specialized structure along the neuronal processes necessary for cell-to-cell communication. In addition, we have evidence that cells carrying the C9ORF72 expansion are more vulnerable to cellular stressors, thereby leading to increased neuronal cell death.
Using ALS/FTD patient-derived adult neurons made from C9ORF72 induced pluripotent stem (iPS) cells we will study the disease mechanisms caused by this expansion in more detail. Specifically, we will investigate whether the repeat expansion in mutant C9ORF72 alters synaptic neuronal proteins, which in turn may explain the increased vulnerability to cellular stress and cell death. We will use state of the art fluorescence microscopy technology to image and visualize neuronal dendrites and synapses to confirm a structural defect in C9ORF72 iPS neurons. We will also determine whether altered RNA processing events are responsible for the observed synaptic dysfunction by genetically manipulating the expression levels of candidate proteins. Finally, we will confirm these findings in novel C9ORF72 mouse models.
These studies will teach us about the underlying mechanisms of mutant C9ORF72-induced dysfunctional RNA processing. To date, no downstream pathways have been identified that may explain RNA processing related to C9ORF72 ALS/FTD disease pathogenesis. The identification of these pathways is crucial in the discovery of novel cellular and molecular targets for future therapeutic development of disorders characterized by the C9ORF72 expansion. Given the high prevalence of the C9ORF72 expansion, finding novel therapeutic targets that are relevant to this expansion will open up greatly needed drug development opportunities for a large patient population.
Is this your first MDA grant?
Yes, this is my first MDA grant as a principal investigator. I am thrilled to be a participating member of MDA and to be able to contribute to the mission of MDA to understand the mechanisms and pathways of ALS and to provide potential novel targets for future therapeutic development.
What inspired you to study ALS?
The fact that there is only one barely efficacious therapeutic available for ALS patients, who with full consciousness experience the wasting of their body over a long period of time. We need to understand this disease better so that we can improve ALS patients’ lives, maintain their independence for as long as possible and hopefully, one day, cure ALS.
What is your area of focus within the ALS field, and why is it important?
I am greatly interested in the synaptic biology of C9ORF72 ALS given that this expansion is also prevalent in different forms of dementias that are characterized by cognitive impairments due to neuronal loss in the cortical regions of the brain.
Most studies in ALS are focused on mechanisms of motor neuron degeneration, and not cortical neuron degeneration. Our studies are aimed to also understand the role of cortical neurons in ALS, which can contribute to the cognitive impairments observed in C9ORF72 ALS patients.
Does your work have any potential implications for other disease fields?
Yes, especially for frontotemporal dementia. But the expansion of C9ORF72 has also been found in other neurodegenerative diseases and dementias, including Alzheimer’s disease.
What do you feel people impacted by ALS can have the most hope about with respect to research right now?
The power of genetics has allowed us to move towards potential therapeutics much faster and more focused than ever before. I strongly believe that current research will lead to novel treatments for ALS patients which will hopefully increase patient survival and the quality of patients’ lives.
To learn more about how MDA research is accelerating treatments and cures for ALS, please visit mda.org/als.
