Neuronal lesions containing abnormal aggregated tau protein constitute one of the diagnostic hallmarks of Alzheimer's disease, related tauopathy disorders, and advanced aging of the brain. In Alzheimer's disease, tau neuropathology correlates with severity of dementia. However the mechanisms by which aggregated tau leads to the dysfunction and loss of neurons in Alzheimer's disease patients remain enigmatic. We previously demonstrated that a conserved gene called sut- 2/MSUT2 controls tau aggregation and toxicity in C. elegans and human cells. Preliminary studies have demonstrated that MSUT2 controls neuronal susceptibility to tau toxicity in the mammalian brain. The proposed work will verify these findings and explore the molecular underpinnings by which MSUT2 acts to modulate tauopathy disease mechanisms. Although MSUT2 appears to bind RNA, the molecular mechanisms of MSUT2 modulation of tauopathy remains unclear.
The Specific Aims of this project are to: 1) Characterize the consequences of MSUT2 knockout in mouse models of tauopathy. 2) Determine the effect of increased MSUT2 activity on tau neuropathology and behavioral phenotypes in mice. 3) Dissect the molecular mechanisms of MSUT2 modulation of tauopathy. Completion of the project as proposed will demonstrate the importance of MSUT2 in tauopathy. We will also gain significant understanding of the molecular mechanisms involved in MSUT2 modulation of tau pathology in diverse organisms ranging from C. elegans to humans. This knowledge will set the stage for future translational studies by providing novel candidate therapeutic targets for pharmacological intervention.
Statement: Alzheimer's disease has no effective treatment and is the 6th leading cause of death in the US. Pathological tau protein accumulates in the brain neurons of Alzheimer's disease patients. Aberrant tau causes neuronal dysfunction and neurodegeneration in Alzheimer's disease and related dementia disorders. The molecular basis underlying the neurotoxicity of tau pathology remains incompletely understood. Preliminary studies have demonstrated that MSUT2 protein acts as an important regulator of neuronal susceptibility to tau pathology. By completing the proposed studies, we will gain understanding of the molecular mechanisms contributing to tau mediated neurodegeneration.
| Wheeler, Jeanna M; Guthrie, Chris R; Kraemer, Brian C (2012) Potential neuroprotective strategies against tauopathy. Biochem Soc Trans 40:656-60 |
