Longitudinal Imaging and Analysis of Neurons Expressing Polyglutamine-Expanded Proteins

Abstract

Misfolded proteins have been implicated in most of the major neurodegenerative diseases, and identifying drugs and pathways that protect neurons from the toxicity of misfolded proteins is of paramount importance. We invented a form of automated imaging and analysis called robotic microscopy that is well suited to the study of neurodegeneration. It enables the monitoring of large cohorts of individual neurons over their lifetimes as they undergo neurodegeneration. With automated analysis, multiple endpoints in neurons can be measured, including survival. Statistical approaches, typically reserved for engineering and clinical medicine, can be applied to these data in an unbiased fashion to discover whether factors contribute positively or negatively to neuronal fate and to quantify the importance of their contribution. Ultimately, multivariate dynamic models can be constructed from these data, which can provide a systems-level understanding of the neurodegenerative disease process and guide the rationale for the development of therapies.