The role NEDD4 and NEDD4-2 in the central nervous system

Nedd4 and Nedd4-2 are E3 ubiquitin ligases that are important components of the ubiquitin proteasome system (UPS). Abnormal activity in the UPS has been implicated to underlie a number of neurological disorders and so there is great interest in understanding the role of specific ligases and their involvement in neuronal processes. To date however, there is very little known in regards to the in vivo physiological implications within the CNS. This study used well characterized tests to assess behaviour in heterozygotes and age-matched wild-type controls. Results from this study found that reductions in brain levels of Nedd4 and Nedd4-2 produced distinct behavioural outcomes. For instance, Nedd4 heterozygous mice show an age-dependent change in gait and cognitive abnormalities. Nedd4-2 heterozygous mice on the other hand do not show any alterations in gait but an age-dependent decline in motor capacity was observed, with normal cognitive function. This study examined some well known neuronal targets for both Nedd4 and Nedd4-2 in context of the behavioural phenotype uncovered. This study is the first to show in vivo of reduced levels of Nedd4 and Nedd4-2, and may provide insight into the potential roles for these two important ligases in neuronal function and a better understanding of development of some neurological diseases.<br>