Seminar

Neuronal Sumoylation and Its Contributions to Form, Function and Neurodegenerative Diseases

Prof. PAUL FRASER

Alzheimer disease (AD) is caused by a number of different factors but the pathological endpoint is always characterized by the deposition of the amyloid-β (Aβ) peptide as senile plaques and the intraneuronal accumulation of tau protein as neurofibrillary tangles. The combination of these toxic features leads to extensive neuronal death and the clinical presentation of memory loss and cognitive impairments. Small ubiquitin-like modifiers (SUMO) are covalently conjugated to target proteins and modulate a growing number of cellular pathways. Our group has linked sumoylation to both amyloid and tangle pathology where SUMO3 over-expression increases Aβ secretion and tau is a target for SUMO1 conjugation. We have recently advanced these investigations by the development of a SUMO1 transgenic mouse model. Immunoprecipitation and mass spectrometry proteomic analysis has revealed many novel SUMO1 cytoskeletal conjugates, including tau, as well as proteins involved in synaptic formation and function. SUMO1 transgenics have also been crossed with an aggressive mouse model of AD-related amyloid pathology (TgCRND8) which displays characteristic amyloid plaques and cognitive impairments. A fear conditioning test of recent memory has indicated that SUMO1 may rescue the memory defects in the TgCRND8 transgenics. These mice represent the first reported SUMO transgenic model and constitute a valuable tool for investigating the contributions of sumoylation to Alzheimer disease and related neurodegenerative disease.