MesoRNAs are involved in many pathways of biological regulation and represent a rich source of cellular RNA diversity and biomarker discovery. Alzheimer’s and Amyotrophic lateral sclerosis (ALS) are widespread neurological diseases that are commonly characterized by protein aggregation in neurons. It is still poorly understood how protein synthesis or other mesoRNA-derived processes play a role in these diseases. This proposal is a collaboration between two PIs with complementary expertise: Pan at U. Chicago is an expert on mesoRNA sequencing technology and in translational regulation, Jin at Emory University is an expert on Alzheimer’s and ALS. We will profile mesoRNAs using our state-of-the-art sequencing technology in the normal and disease human tissues and blood to identify dysregulation of mesoRNAs and their modifications in these diseases. Our study will be the first of its kinds into the protein synthesis and other aspects of mesoRNA biology in these human diseases and for biomarker discovery. This initial phase of study will be followed up with large-scale clinical investigations and mechanistic understanding in animal models.