Presenting Author:
Principal Investigator:
Department:
Neurology, Ken and Ruth Davee Department
Keywords:
Corticospinal motor neuron, Transactive Response (TAR) DNA binding protein (TDP-43), Amyotrophic Lateral Sclerosis
Location:
Third Floor, Feinberg Pavilion, Northwestern Memorial Hospital
B108 - Basic Science
Precise cellular analysis of corticospinal motor neuron in hTDP-43A315T mice
Corticospinal motor neurons (CSMN) are unique in their ability to collect and integrate signals from different regions of the cerebral cortex, and to transmit this information to distinct segments of the spinal cord. Their proper function is thus pivotal for motor functions, and CSMN degeneration is an important aspect of motor neuron diseases, in which voluntary movement is impaired. Transactive Response (TAR) DNA binding protein 43 (TDP-43) is an evolutionarily conserved DNA/RNA binding nucleoprotein involved in various functions, most importantly in RNA metabolism. Numerous mutations in the conserved region of TDP-43 have been detected in sporadic and familial cases of ALS patients. Of all the mouse models generated to date, the one overexpressing the hTDP-43A315T mutation under the control of the prion promoter recapitulates many aspects of ALS pathology. Here, we investigate the health and stability of CSMN that express mutant TDP-43 and display TDP-43 pathology. We previously generated and characterized UCHL1-eGFP mice, in which CSMN are genetically labelled with eGFP expression that is stable and long lasting. Now, in an attempt to distinguish CSMN from other neurons and cells in the cerebral cortex, and to study their cell biology with high precision and clarity, we generated a CSMN reporter line of TDP-43A315T by crossing UCHL1-eGFP and hTDP-43A315T mice. Our ongoing studies suggest that CSMN undergo progressive degeneration in the presence of TDP-43 pathology, and CSMN loss is accompanied by compromised motor behavior, such as poor performance on a rotating rod and weak hind limb strength. Increased astrogliosis and microgliosis display an evoked immune response in the motor cortex, and immunohistochemistry coupled with electron microscopy reveals mitochondrial aggregation as well as cyto-architectural defects. RNA-Seq analysis of FACS purified healthy and diseased CSMN provides unique insights into the differentially regulated gene pathways in diseased CSMN, and enables identification of canonical pathways that are selectively modulated with respect to TDP-43 pathology, as well as potential alternative splice variations of key genes. Upon completion, our studies will reveal the unique importance of the TDP-43A315T mutation on CSMN vulnerability and progressive degeneration.
