Title: Investigating selective vulnerability in C9orf72 positive amyotrophic lateral sclerosis using induced pluripotent stem cell derived motor and sensory neurons
Funder: The Academy of Medical Sciences

Abstract: Aim: Identification of phenotypic and transcriptional differences between iPSC-derived motor and sensory neurons with C9orf72 mutations to provide insights into the relative selective vulnerability of motor neurons in amyotrophic lateral sclerosis. Objectives: I will compare activation of proapoptotic pathways, evaluate the stress granule response at basal conditions and following oxidative stress and will compare multiple axonal transport modalities using commercially available markers of lysosomal, RNA and mitochondrial transport. Finally, I will assess transcript abundance in the axonal and somatodendritic component using unbiased RNA sequencing methods. Background: Amyotropic Lateral Sclerosis is a progressive disease resulting in the selective degeneration of corticospinal tract and alpha motor neurons in particular, its cause and selectivity remain poorly understood. Most cases are sporadic, but 10% of patients have autosomal inheritance, most commonly a hexanucleotide expansion in C9orf72, accounting for up to 50% of inherited ALS. Multiple laboratories, including ours, have developed human motor neuron models based on the C9orf72 hexanucleotide expansion using induced pluripotent stem cell technology and have demonstrated reproducible cellular phenotypes. Impact: By comparing the two cell types, which share similarities in the human body and in vitro, including a peripheral course and similar length, I will aim to understand if phenotypes secondary to the C9orf72 mutation have mechanistic importance for cell-specific vulnerability of motor neurons, or if they are seen more widely in neurons, including those not typically affected during the disease course. These findings will be of importance for the interpretation of the cellular phenotypes discovered in motor neurons until now.

Lay abstract: Motor neuron disease is an incurable illness that results in death through paralysis, most commonly 2.5 years from the first onset of symptoms. This occurs due to the death of motor neurons, which are nerve cells responsible for movement. Importantly, the nerve fibres responsible for sensation and eye movements, amongst others, are not involved. Why motor neuron disease specifically targets motor nerves remains unknown. While there is no specific cause for the condition in most patients, a minority will inherit a genetic defect in the gene C9orf72 that causes motor neuron disease. A genetic defect causing a condition is very helpful for scientists to study and provides special insight into the disease. Skin cells from patients with the C9orf72 mutation can be converted initially into stem cells, and then into motor nerves, allowing us to study how the mutation causes abnormalities that are thought to be important in the development of motor neuron disease. Because scientists have thus far been interested mostly in growing the affected nerve cell types, it is not known whether the abnormalities we see in the motor nerves from patients with the C9orf72 mutation can also be found in other similar cell types. Finding abnormal features in motor nerves but not sensory nerves, could give clues about why motor nerves die, and why other nerve cells survive. To answer this question I will grow and study sensory nerves with the C9orf72 mutation, which are similar in length, and compare their properties and abnormalities to motor nerves.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL