Unique molecular features and cellular responses differentiate two populations of motor cortical layer 5b neurons in a preclinical model of ALS
Maria V. Moya,
Rachel D. Kim,
Meghana N. Rao,
Bianca A. Cotto,
Sarah B. Pickett,
Caroline E. Sferrazza,
Nathaniel Heintz,
Eric F. Schmidt
Affiliations
Maria V. Moya
Laboratory of Molecular Biology, The Rockefeller University, 1230 York Avenue, Box 260, New York, NY 10065, USA
Rachel D. Kim
Laboratory of Molecular Biology, The Rockefeller University, 1230 York Avenue, Box 260, New York, NY 10065, USA
Meghana N. Rao
Laboratory of Molecular Biology, The Rockefeller University, 1230 York Avenue, Box 260, New York, NY 10065, USA
Bianca A. Cotto
Laboratory of Molecular Biology, The Rockefeller University, 1230 York Avenue, Box 260, New York, NY 10065, USA
Sarah B. Pickett
Laboratory of Molecular Biology, The Rockefeller University, 1230 York Avenue, Box 260, New York, NY 10065, USA
Caroline E. Sferrazza
Laboratory of Molecular Biology, The Rockefeller University, 1230 York Avenue, Box 260, New York, NY 10065, USA
Nathaniel Heintz
Laboratory of Molecular Biology, The Rockefeller University, 1230 York Avenue, Box 260, New York, NY 10065, USA; Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA
Eric F. Schmidt
Laboratory of Molecular Biology, The Rockefeller University, 1230 York Avenue, Box 260, New York, NY 10065, USA; Corresponding author
Summary: Many neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), lead to the selective degeneration of discrete cell types in the CNS despite the ubiquitous expression of many genes linked to disease. Therapeutic advancement depends on understanding the unique cellular adaptations that underlie pathology of vulnerable cells in the context of disease-causing mutations. Here, we employ bacTRAP molecular profiling to elucidate cell type-specific molecular responses of cortical upper motor neurons in a preclinical ALS model. Using two bacTRAP mouse lines that label distinct vulnerable or resilient projection neuron populations in motor cortex, we show that the regulation of oxidative phosphorylation (Oxphos) pathways is a common response in both cell types. However, differences in the baseline expression of genes involved in Stem and the handling of reactive oxygen species likely lead to the selective degeneration of the vulnerable cells. These results provide a framework to identify cell-type-specific processes in neurodegenerative disease.
