Drug Discovery to Ameliorate Proteostasis Failure in Tauopathies

Public abstract:

A common feature of tauopathies is protein aggregation, neuronal dysfunction and cell death. These events are age-dependent and not observed in the brains of healthy young individuals. We have proposed that the functional health of the neuronal proteome is regulated by the proteostasis network (PN) that controls protein synthesis, protein folding and assembly, and degradation. The studies proposed here with the Tau Consortium are to establish how the PN protects and prevents Tau aggregation in cellular health and fails in aging. To accomplish this, we propose to develop and validate a collection of proteostasis sensors that report on each arm of the PN to obtain a quantitative readout of the effects of Tau expression on cellular function. These sensors will be used to test small molecule proteostasis regulators to restore the cellular PN and prevent Tau aggregation and the cellular consequences of proteostasis failure. In Aim 1, we will employ a combination of biological systems including C. elegans and human tauopathy neuronal cell models for the expression of live cell reporters to functionally measure each arm of the PN. These models will also allow us to interrogate the effects of aging in direct differentiated neurons and C. elegans, and to monitor how genetic pathways that regulate aging and the PN are affected by mutant Tau. Aim 2 will use these human cell and animal model systems to assess the ability of different combinations of small molecule proteostasis regulators to restore the cellular PN and reduce TAU proteotoxicity. We posit that the unique richness of approaches afforded by this project together with the efforts of the Kelly laboratory and with other members of the Tau Consortium (including Gestwicki, Rubinsztein, Cuervo and Prusiner) that are also developing and characterizing small molecule proteostasis regulators will together provide a mechanistic understanding on the events during proteostasis failure in aging and identify targets for therapeutic development to alter the course of TAU mismanagement in neurodegenerative disease. To ensure that other members of the Tau Consortium benefit from our tool development and small molecule studies, we will establish a process for active sharing all of our reagents and tools.

Lay description:

These studies are to understand how the proteostasis network protects and prevents Tau aggregation. We will develop a collection of proteostasis reporters to quantify each arm of the proteostasis network in human neuronal and animal models of Tauopathy, to determine when molecular failure occurs leading to Tau aggregation, and use these reporters to test and validate small molecules that modulate the proteostasis network to restore cellular function and reduce TAU proteotoxicity.