The Agar group characterizes post-translational modifications of proteins and changes in protein, peptide, and lipid expression that occur during ALS, and then determines which of these changes have structural or toxic consequences. We use a variety of techniques but are best known for our contibutions to top-down mass spectrometry development. We are now developing a potential drug for ALS based upon these studies.
Our research involves target discovery, validation, and preclinical therapy development in ALS (and recently other neurodegenerative diseases like Parkinson’s).
The mechanism for how >180 different mutations in Cu-Zn superoxide dismutase (SOD1) caused familial amyotrophic lateral sclerosis (fALS) was unknown. We developed a physicochemical/structural model that implicated aggregation and destabilization of SOD1 as major fALS risk factors. We extended this model to sporadic (idiopathic) ALS using a combination of mass spectrometry of patient’s tissues and neurotoxicology assays. These studies led to the hypothesis, and subsequent in vitro validation, that disease-related SOD1 could be stabilized by a Cys-selective (homo bi-functional) crosslinker.
Unfortunately, previous cross-linkers were too toxic for in vivo (therapeutic) use. We therefore developed a less toxic cross-linker, cyclic thiosulfinates, and demonstrate their efficacy in an ALS mouse model. These highly tunable S-cross-linkers solved a general problem by avoiding the toxic “dead-end” modifications that plagued previous cross-linkers, and as a result have many applications beyond SOD1 stabilization.