Alexander Lenail

The paradox of brain aging is that neurons reduce their transcription of key homeostasis genes late in life. Genes essential for proteostasis, mitochondrial turnover, and heterochromatin maintenance are downregulated in aging neurons, all while proteins aggregate, mitochondria degrade, and the epigenome erodes. This naturally raises the question: is it sufficient to restore neurons’ expression of homeostasis genes to restore their function in old age? We propose to chart the landscape of TF-driven neuronal repair by computationally predicting and experimentally characterizing the transcriptional effects of diverse combinations of pro-homeostasis transcription factors. We hope this work will pave the way for a gene therapy approach to forestall age-related neurodegenerative diseases such as Alzheimer’s, Parkinson’s, ALS, and Huntington’s.