Driving Therapeutic Innovation in Neurodegenerative Disease with Hydrogen Deuterium eXchange Mass Spectrometry

Abstract

Human neurodegenerative conditions such as Parkinson's and Alzheimer's Disease are characterized by the formation and deposition of toxic protein species which exacerbate neuronal dysfunction, impacting the structure and function of the healthy brain. Deciphering the mechanisms underlying protein (mis)folding and aggregation is not only essential for a more coherent view of neurodegeneration, but also crucial for the development of novel therapeutics targeting this family of disorders. Key pathological drivers of neurodegeneration, such as alpha-synuclein and tau proteins, have traditionally proved extremely challenging to characterize structurally due to their intrinsic and widespread structural plasticity. Hydrogen-Deuterium eXchange Mass Spectrometry (HDX-MS) has emerged as a powerful tool to help circumvent this, owing to its ability to capture protein intrinsic disorder in solution, in addition to the transient structural conformations that typify protein aggregation pathways. This review brings together the most recent research where HDX-MS has shed light on mechanisms of neurodegeneration. We highlight how the technique has been successfully integrated into therapeutic development workflows targeting some of the most prevalent neurodegenerative diseases.

Keywords: Drug Discovery; HDX-MS; Neurodegeneration; Structural Proteomics; Therapeutics.