Our laboratory aims to understand how proteostasis machinery in neurons control activity-dependent and stress induced changes in the function, physiology and health of the nervous system. Using mammalian primary neuronal cultures and brain tissue we combine multi-disciplinary approaches that include biochemistry, proteomics, molecular biology, cellular biology and neuronal calcium imaging. Through our efforts we have now discovered a novel nervous-system specific membrane associated proteasome complex that degrades intracellular protein into extracellular peptides with the capacity to potently and specifically modulate neuronal signaling (Ramachandran KV and Margolis, Nat Struct Mol Biol 2017). This discovery of the neuronal membrane proteasome complex (NMP) has revealed a new signaling paradigm and led to the identification of a unique class of neuronal signaling molecules in the form of peptides within the nervous system. Current efforts are being made to understand the molecular mechanisms that control the assembly of this complex, the intracellular source of these peptides and how peptides mediate specific signaling within the nervous system relevant to brain function in health and disease.