Genome wide analysis reveals heparan sulfate epimerase modulates TDP-43 proteinopathy

by Nicole F. Liachko, Aleen D. Saxton, Pamela J. McMillan, Timothy J. Strovas, C. Dirk Keene, Thomas D. Bird, Brian C. Kraemer Pathological phosphorylated TDP-43 protein (pTDP) deposition drives neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). However, the cellular and genetic mechanisms at work in pathological TDP-43 toxicity are not fully elucidated. To identify genetic modifiers of TDP-43 neurotoxicity, we utilized aCaenorhabditis elegans model of TDP-43 proteinopathy expressing human mutant TDP-43 pan-neuronally (TDP-43 tg). In TDP-43 tgC.elegans, we conducted a genome-wide RNAi screen covering 16,767C.elegans genes for loss of function genetic suppressors of TDP-43-driven motor dysfunction. We identified 46 candidate genes that when knocked down partially ameliorate TDP-43 related phenotypes; 24 of these candidate genes have conserved homologs in the human genome. To rigorously validate the RNAi findings, we crossed the TDP-43 transgene into the background of homozygous strong genetic loss of function mutations. We have confirmed 9 of the 24 candidate genes significantly modulate TDP-43 transgenic phenotypes. Among the validated genes we focused on, one of the most consistent genetic modifier genes protecting against pTDP accumulation and motor deficits was the heparan sulfate-modifying enzymehse-5, theC.elegans homolog of glucuronic acid epimerase (GLCE). We found that knockdown of humanGLCE in cultured human ce...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research