The Optimization and Application of Matrix-Assisted Laser Desorption/Ionization Imaging Mass Spectrometry to a Metabolic Study of Huntington’s Disease for the Development of Disease-Altering Treatment

Abstract

Huntington’s Disease (HD) is an autosomal dominant, neurodegenerative disorder, characterized by a variety of motor, sensory, executive, and psychiatric symptoms that ultimately lead to death around 20 years after onset. There are currently no approved treatments that can slow or prevent the progression of HD. Pharmaceutically addressing HD-dependent alterations in cellular metabolism that are linked to pathogenesis has potential as a disease-modifying therapy. While most common techniques for assessing these metabolic changes lack spatialized and cell-specific data that is vital for a pathophysiological study of HD, Matrix-Assisted Laser Desorption/Ionization Imaging Mass Spectrometry (MALDI-IMS) retains the spatial localization of metabolites, differentiating by cell-type and anatomical region. MALDI-IMS procedures and methods were optimized for the detection of nicotinamide adenine dinucleotide (NAD), cholesterol, arachidonic acid (AA), and docosahexaenoic acid (DHA) because of their dysregulation by HD. MALDI method development processes on the target plate were automated and then used to select matrices for optimization as binary mixtures. Detection by matrix mixtures was only enhanced for some metabolites. Detection of NAD in standard and an NAD fragment in tissue suggest detecting intact NAD in tissue by MALDI-IMS is possible. Cholesterol, AA, and DHA were successfully detected using silver nitrate as a MALDI matrix in wildtype tissue. This work broadens the application of MALDI-IMS to metabolic studies of HD for disease-modifying therapies.