Discordant Protein RNA Expression as a Novel Metric of ALS Pathophysiology
Abstract
Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the death of motor neurons in the brain and spinal cord, typically occurring in late adulthood, for which there is no cure. Patients face an average of three years of life remaining. ALS is a challenging disease to treat due to many unknown factors. First, there is a high level of variability among ALS patients as to which region of their body first experiences paralysis. For instance, some patients have trouble speaking and swallowing, while others experience paralysis in their legs. It is unknown whether the motor neuron dysfunctions occurring in the distinct regions in the brain and spinal cord controlling these different movements are the same or different. If motor neurons located in the hindbrain degenerate in a different way than motor neurons in the lumbar spinal cord, then this would determine that two ALS patients should receive different treatments instead of a one-size-fits-all treatment. Second, it is unclear if different types of genetic mutations cause ALS to work in the same way as each other, even if two patients with different genetic mutations experience motor dysfunction in the same part of the body. Most ALS patients carry no known genetic mutations causing ALS, and it is unclear whether these patients undergo the same molecular mechanisms as genetic ALS patients in arriving at the disease state. Third, researchers have been able to create diseased motor neurons-in-the-dish models of ALS using patient stem cells, but it is unclear how accurately these stem cell-based cultures represent real adult motor neurons in the human body, since they mostly resemble embryonic tissues. To test their accuracy, their gene expression activity must be compared to adult brain and spinal cords measured in humans, which are accessible only from deceased patients after they have donated their bodies to research. Finally, current technologies to simultaneously measure gene expression activity at the RNA and protein levels have only been analyzed separately, and the natural variation in expression for some genes makes their disruption in ALS difficult to detect. We propose a novel and more sensitive method of analyzing RNA and protein abundances to better understand which RNA molecules produce protein products, and how this processing is disrupted in ALS patients. This project aims to measure RNA and protein levels in different regions of the human brain and spinal cord that contain the motor neurons responsible for controlling movement throughout different parts of the body. It will also measure how these RNA and protein levels are disturbed in ALS patients who carry a known ALS gene mutation, known as C9orf72 hexanucleotide repeat expansion, as well as in patients who do not carry any ALS gene mutations. By understanding how motor neurons in different brain regions express RNA and protein, we may be able to explain why each ALS patient suffers loss of motor functions in specific parts of their body and, as a result, which treatment is best suited for them. Understanding the activity of genes in adult tissues will also provide a road map to researchers who seek to recreate the motor neuron degeneration in the petri dish using ALS patient stem cells. This would enable them to create stem cells from the blood of a young, pre-symptomatic patient who carries an ALS gene mutation, create motor neurons in the dish and observe how they degenerate, test thousands of possible drug treatments on those motor neurons in the dish (instead of the patient) to find the best possible way to prevent degeneration, and deliver the best drug for that patient so that they never have to experience the onset of ALS. This scenario exemplifies predictive, preventive, and personalized medicine. The experiments proposed for this project aim to help realize this scenario, and by using more sensitive analyses to observe the relationship bet
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210299
Entities
People
- Ritchie Ho
Organizations
- Cedars-Sinai Medical Center
- United States Army