Many if not all neurodegenerative diseases are characterized by pathological aggregates, such neurofibrillary tangles, senile plaques, or Lewy bodies. These pathological aggregates contain misfolded proteins, including tau, alpha-synuclein, or TDP-43. What are the mechanisms by which misfolded/aggregated proteins in neurodegenerative diseases? One approach that we pioneered based upon work that began in the mid 1990s was based on use of invertebrate genetics. If human neurodegenerative disease-associated transgenes can be successfully expressed in fly tissues, and if such misexpression can produce abnormal phenotypes, whether morphological, behavioral, or electrophysiological, than the toolkit of invertebrate genetics can be used in order to identify signaling networks that regulate production of this phenotype. A subset of such identified networks are likely to also play a role in producing disease pathology in humans as well as in flies. Some of the genes identified may in fact themselves be disease genes!

Over the last 15 years, studies from our laboratory, as well as the work other investigators around the world have showed the utility of this unbiased approach toward dissection of disease mechanisms. In many instances, however, the phenotypes produced have been disappointing. Our recent work suggests that insect codon-optimized transgenes produce more useful and robust phenotypes.

A second theme of our work derives from close collaborations with the laboratory of Dr. Rakez Kayed and are focused on analysis of the role of oligomeric species of disease-associated proteins in pathogenesis, as well as the use of novel conformation-specific monoclonal antibodies and single chain fragment variable constructs derived from these antibodies.