Disease Mechanisms in ALS [a Single Nuclei Sequencing Study of Patient-derived Material]

Amyotrophic Lateral Sclerosis (ALS) is rare, fatal, neurodegenerative disorder primarily affecting the motor system with degeneration of upper and lower motor neurons. This leads to progressive muscle weakness limiting survival to 2 – 5 years after disease onset. Other brain regions can be affected as well, in particular the frontotemporal regions in up to 50% of patients. ALS is a hereditary disorder in 10-15% of patients, with mutations in the gene encoding C9orf72 being the most common cause of ALS. The cause of the disease remains elusive in the majority of patients. With the advent of technologies that allow the quantification of RNA transcripts and protein levels in patient-derived materials, there is an increased interest in studying post-mortem brain and spinal cord samples from ALS patients and controls in order to elucidate disease mechanisms. It is known that ALS is a non-cell autonomous disease in which not only the motor neurons are diseased, but also neighboring glial cells such as microglia, astrocytes and oligodendrocytes. In this project we will use single nuclei sequencing of post-mortem brain and spinal cord samples to characterize the changes in transcript levels in different cell types in the motor cortex and spinal cord from patients with sporadic ALS, C9orf72-mediated ALS and controls. This approach will allow us to identify altered pathways in neurons and glial cells from ALS patients and may give rise to future biomarker studies and further mechanistic research about disease mechanisms of ALS.