| RRC ID |
59537
|
| Author |
Liachko NF, Saxton AD, McMillan PJ, Strovas TJ, Keene CD, Bird TD, Kraemer BC.
|
| Title |
Genome wide analysis reveals heparan sulfate epimerase modulates TDP-43 proteinopathy.
|
| Journal |
PLoS Genet
|
| Abstract |
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 a Caenorhabditis elegans model of TDP-43 proteinopathy expressing human mutant TDP-43 pan-neuronally (TDP-43 tg). In TDP-43 tg C. elegans, we conducted a genome-wide RNAi screen covering 16,767 C. 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 enzyme hse-5, the C. elegans homolog of glucuronic acid epimerase (GLCE). We found that knockdown of human GLCE in cultured human cells protects against oxidative stress induced pTDP accumulation. Furthermore, expression of glucuronic acid epimerase is significantly decreased in the brains of FTLD-TDP cases relative to normal controls, demonstrating the potential disease relevance of the candidate genes identified. Taken together these findings nominate glucuronic acid epimerase as a novel candidate therapeutic target for TDP-43 proteinopathies including ALS and FTLD-TDP.
|
| Volume |
15(12)
|
| Pages |
e1008526
|
| Published |
2019-12-1
|
| DOI |
10.1371/journal.pgen.1008526
|
| PII |
PGENETICS-D-19-00919
|
| PMID |
31834878
|
| PMC |
PMC6934317
|
| MeSH |
Animals
Animals, Genetically Modified
Autopsy
Brain / metabolism
Caenorhabditis elegans
Caenorhabditis elegans Proteins / genetics*
Caenorhabditis elegans Proteins / metabolism
Carbohydrate Epimerases / genetics*
Carbohydrate Epimerases / metabolism
Cell Line
DNA-Binding Proteins / genetics*
DNA-Binding Proteins / metabolism
Disease Models, Animal
Down-Regulation
Gene Knockdown Techniques
HEK293 Cells
Humans
RNA Interference
Reverse Genetics
TDP-43 Proteinopathies / genetics*
TDP-43 Proteinopathies / metabolism
|
| IF |
5.224
|
| Times Cited |
0
|
| Resource |
| C.elegans |
tm472
tm1156
tm3262
tm5935
tm2166
tm924 |
