Presenting Author:
Megan Schultz, B.S.
Principal Investigator:
Department:
Neurology, Ken and Ruth Davee Department
Keywords:
Corticospinal motor neurons (CSMN), neurodegenerative diseases, amyotrophic lateral sclerosis (ALS), Alsin 2 (ALS2) gene... [Read full text]
Location:
Third Floor, Feinberg Pavilion, Northwestern Memorial Hospital
B106 - Basic Science
AlsinKO-UeGFP mice, display CSMN-specific cellular defects without major cell loss.
Corticospinal motor neurons (CSMN) are unique in their ability to collect, integrate, translate and transmit cerebral cortex’s input towards spinal cord targets. Their degeneration is the key in numerous neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). Mutations in the Alsin 2 (ALS2) gene are reported to be responsible for juvenile primary lateral sclerosis, infantile onset ascending hereditary spastic paraplegia, and are the most common cause for autosomal recessive juvenile ALS. In addition, upper motor neuron signs and bulbar symptoms are often prevalent in patients with juvenile ALS. However, cellular and molecular aspects of CSMN degeneration has not been studied in detail due to lack of selective markers to visualize these neuron populations in vivo. By crossing UCHL1-eGFP with AlsinKO, we generated AlsinKO-UeGFP mice, a CSMN reporter line to investigate upper motor neuron defects in the absence of Alsin. This novel reporter line helped us visualize and study CSMN at different stages of disease progression. Different from the hSOD1G93A mice or the TDP-43 mouse models, the numbers of CSMN do not show dramatic reduction in the absence of Alsin. However, detailed cellular analysis using immunocytochemistry coupled with electronmicroscopy (EM) revealed very precise aspects of cellular defects that are restricted to CSMN. We find that even though CSMN do not undergo massive cell loss, the neurons are not healthy. The apical dendrites of CSMN become vacuolated, and this cellular defect is observed only in CSMN in the motor cortex. In addition, there are defects in the mitochondria, and there are signs of defective autophagy, with enlarged lysosomes that contain defective mitochondria, in addition to other proteins. The integrity of the cell membrane is impaired and becomes leaky especially towards end-stage. These findings suggest that Alsin is an important protein for proper CSMN function, and in its absence CSMN display precise neuronal defects, but such defects do not initiate their clearance. Therefore, even though the neurons are still present at layer V of the motor cortex, they are unhealthy and potentially nonfunctional.
