An atfs-1 loss-of-function screen identifies novel regulators of α-synuclein toxicity in C. elegans dopaminergic...

Overexpression of α-synuclein (α-syn), an inherently disordered protein, triggers chronic activation of the mitochondrial unfolded protein response (UPRmt) pathway in Caenorhabditis elegans with enhanced dopaminergic (DAergic) neurodegeneration. Introduction of a loss-of-function(lf) mutation in atfs-1, the main transcriptional regulator of the UPRmt, into α-syn nematodes results in significant neuroprotection from α-syn-induced DA neuron loss. Using this sensitized neuroprotective background, we performed a F3 forward genetic screen in C. elegans atfs-1(lf) mutants to identify molecular components associated with the modulation of neurodegeneration in α-syn-expressing DA neurons. Homozygous mutant animals were examined for enhanced neurodegeneration; multiple independent alleles were uncovered. Among these, we identified new nonsense alleles encoding the histone lysine demethylases (H3K27me3) jmjd-1.2 (orthologous to human KDM7A, PHF2, and PHF8) and jmjd-3.1 (homologous to yeast CYC8). Another line carried a nonsense allele of twk-14. This gene encodes a conserved protein termed KCNK12 in mammals that facilitates passive background K+ leak currents to set and stabilize resting membrane potential. To further examine the association of these gene products in DA neurodegeneration, we used neuron-specific RNA interference, mutants, or both. DA neurodegeneration was observed in the α-syn + atfs-1(lf) background when jmjd-1.2, jmjd-3.1, or twk-14 were individually depleted. These results provide evidence that jmjd-1.2 and jmjd-3.1, which encode previously characterized H3K27me3 demethylases, and the uncharacterized twk-14 gene product, orthologous to human KCNK12, naturally confer protection from α-syn-induced neurotoxicity.