Genetic modifiers in a model tauopathy

The formation of abnormal inclusions made of only a handful of proteins is believed to be central to the vast majority of cases of neurodegeneraive disease in man. Of these proteins, tau is implicated in a wide variety of diseases, including Alzheimer s disease, progressive supranuclear palsy, corticobasal degeneration, Pick s disease, argyrophilic grain disease and familial forms of frontotemporal dementia. The development of robust transgenic mouse models for these so-called tauopathies has made it possible to dissect the pathway leading from normal, soluble to abnormal, insoluble tau protein. We propose to identify proteins that modify (enhance or suppress) neurodegeneration in mouse models of human tauopathy. This may in turn lead to novel insights into possible prevention and treatment of these so far incurable diseases.

Abundant filamentous inclusions made of the microtubule-associated protein tau in a hyperphosphorylated state are a defining feature of a number of neurodegenerative diseases collectively referred to as tauopathies. The identification of mutations in the tau gene as the cause of a familial form of dementia has established that dysfunction of tau is sufficient to cause neurodegeneration and dementia. It has also led to the development of good transgenic mouse models for the human tauopathies. We have produced mouse lines transgenic for mutant human P301S tau protein. These lines reproduce the essential molecular and cellular features of the human tauopathies, including the formation of abundant filaments made of hyperphosphorylated tau protein and neurodegeneration. We now propose to use ethyl N-nitrosourea (ENU) mutagenesis to identify modifiers of the neurodegenerative phenotype, taking advantage of the progressive impairment in motor function that these mice develop.