Science; doi:10.1126/science.1245296

Science; doi:10.1126/science.1245321

Parkinson's disease (PD) is associated with pathological aggregation of α-synuclein (α-syn), with certain alleles, such as the autosomal dominant A53T mutation, causing prominent disease and dementia. Several models of PD exist, including a yeast model in which α-syn expression results in toxicity and an induced pluripotent stem cell (iPS)-based model derived from a patient harboring A53T. Chung et al. explored a finding from a previous yeast screen linking a nitrosative stress response transcriptional regulator, Fzf1, and suppression of α-syn toxicity. They now find that α-syn expression in both yeast and A53T iPS-derived cortical neurons induces protein nitration and perinuclear NO distribution and that expression of Fzf1 decreased the induced nitration in yeast. Manipulating NO levels in the neurons led to an altered unfolded protein response, a known component of PD. Tardiff et al. pursued a compound, NAB2, which was found by screening for the suppression of toxic levels of another neurodegenerative disease-linked protein, TDP-43. The compound could reverse several α-syn–induced phenotypes, including normalization of NO levels in A53T neurons. Using several genetic approaches, the authors determined the NAB2 target to be the E3 ligase Nedd4 and found that NAB2 could promote Nedd4-dependent processes, including vesicular traffic of specific cargo proteins and bulk endosomal transport. These results suggest that NAB2 rescues these seemingly disparate phenotypes associated with α-syn toxicity by activating the Nedd4 pathway.