Project Summary/Abstract REGg Regulation of Tau Protein The proposed study will focus on regulation of Tau protein by the REGg proteasome and its causal relation to dementia. Tau is a set of isoforms that are microtubule-associated proteins that become hyperhosphorylated and form ’tangles’ in dementia. The common theme for Alzheimer’s Disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and primary ‘tauopathies’ is abnormal deposition of protein, either intracellularly or extracellulary. Tau deposits are seen in AD and primary tauopathies, and Tau deposits appear to be the most accurate predictor of cognitive decline in AD. Thus, a loss of regulation of protein turnover by proteasome action and maintenance of protein homeostasis—proteostasis—appears to be common to dementias. Our group has pioneered work on the 20S proteasome, REGg. This proteasome is ATP- and Ubiquitin-independent and processes regulatory cellular components, including transcriptional coregulators. Our findings indicate REGg is a key player in homeostasis of Tau. We have developed a REGg knockout (KO) mouse and a REGg overexpressing (OE) mouse. Using these, with commercially available Tau-overexpressing mice, we have found that: (1) the REGg proteasome digests Tau and phosphorylated Tau, implicating it in Tau proteostasis, (2) the REGg KO mouse has decreased numbers of neurons in the hippocampus and decreased dendrite formation compared to normal mice and (3) REGg KO mice have slower learning at 8 months than normal mice. These findings indicate that REGg is central in maintenance of brain neurons. Recently we have defined a negative regulator of REGg, NIP30, and found a conserved motif that is phosphorylated (‘off’ for REGg) or not (‘on’). We have constructed phosphor-mimetic or phosphor-negative knock-in ‘on’ or ‘off’ model mice. With these observations and tools in hand, the proposed work will test the hypothesis that REGg is required in proteostasis of Tau and loss of its activity leads to Tau accumulation in neurons. Our efforts will include: a) characterization of phosphorylated Tau as a target of REGg in vivo and in vitro, b) determining the mechanisms of Tau degradation by REGg, and c) determining behavioral and learning traits that are modulated by REGg activity. The proposed work is novel and highly feasible. Successful outcome of the studies will give us ability to measure onset of neuronal decay at earlier stages than we presently can, and define neurodegenerative mechanisms related to proteostasis.