Condensate-mediated organization of the gene expression machinery in healthy and diseased neurons
Controlling what genes are turned on or off —gene expression —is frequently dysregulated in neurodegeneration and aging. A key step in gene expression is organizing the machinery turning genes on or off in enigmatic assemblies within cells known as condensates. Neurons are masters of using condensates in unique ways to regulate their complex and demanding gene expression programs. However, these specialized mechanisms of condensate-mediated organization may also make some neurons selectively vulnerable to diseases that disrupt the proteins responsible for this organization.
A striking example is amyotrophic lateral sclerosis (ALS), a devastating disease that selectively affects motor neurons, leading to paralysis and death. In nearly all ALS cases, the protein TDP-43, which contains a floppy protein tail and forms condensates in the nucleus of cells, mislocalizes to the cytoplasm where it forms aberrant condensates through its floppy tail. While most of what we know about TDP-43 relates to its function as an RNA-binding protein in disease, its function as a DNA-binding protein regulating gene expression in healthy neurons remains poorly understood.
My project investigates the function of TDP-43 in the nucleus of healthy motor neurons to better understand its malfunction in neurodegeneration. My approach is to decipher what nuclear proteins interact with condensates of the floppy tail of TDP-43, and to determine how these proteins work together to regulate gene expression in motor neurons. Ultimately, I will establish how the machinery and genes regulated by TDP-43 condensates in healthy neurons are dysregulated in neurodegeneration. This work is significant because it will reveal the mechanisms behind why some neurons are especially susceptible to the malfunction of specific proteins by elucidating the role of these proteins in healthy neurons, which holds the promise of finding new therapeutic opportunities for neurodegeneration.
