Downregulation of Hsp90 and the antimicrobial peptide Mtk suppresses poly(GR)-induced neurotoxicity in C9ORF72-ALS/FTD

• Published in: Neuron (Cambridge, Mass.) Vol. 111; no. 9; pp. 1381 - 1390.e6
• Main Authors: Lee, Soojin, Jun, Yong-Woo, Linares, Gabriel R., Butler, Brandon, Yuva-Adyemir, Yeliz, Moore, Jill, Krishnan, Gopinath, Ruiz-Juarez, Bryan, Santana, Manuel, Pons, Marine, Silverman, Neal, Weng, Zhiping, Ichida, Justin K., Gao, Fen-Biao
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.05.2023
• Subjects: ALS; Amyotrophic Lateral Sclerosis - genetics; Animals; antimicrobial peptide; C9ORF72; C9orf72 Protein - genetics; C9orf72 Protein - metabolism; Dipeptides - genetics; Disease Models, Animal; DNA Repeat Expansion; Down-Regulation; DPR; Drosophila - metabolism; Frontotemporal Dementia - genetics; Frontotemporal Dementia - metabolism; FTD; Hsp90; Motor Neurons - metabolism; Mtk; neurodegeneration; poly(GR); TopoII; Hsp90; Mtk; FTD; DPR; ALS; neurodegeneration; antimicrobial peptide; C9ORF72; poly(GR); TopoII
• ISSN: 0896-6273; 1097-4199; 1097-4199
• DOI: 10.1016/j.neuron.2023.02.029

GGGGCC repeat expansion in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat RNAs can be translated into dipeptide repeat proteins, including poly(GR), whose mechanisms of action remain largely unknown. In an RNA-seq analysis of poly(GR) toxicity in Drosophila, we found that several antimicrobial peptide genes, such as metchnikowin (Mtk), and heat shock protein (Hsp) genes are activated. Mtk knockdown in the fly eye or in all neurons suppresses poly(GR) neurotoxicity. These findings suggest a cell-autonomous role of Mtk in neurodegeneration. Hsp90 knockdown partially rescues both poly(GR) toxicity in flies and neurodegeneration in C9ORF72 motor neurons derived from induced pluripotent stem cells (iPSCs). Topoisomerase II (TopoII) regulates poly(GR)-induced upregulation of Hsp90 and Mtk. TopoII knockdown also suppresses poly(GR) toxicity in Drosophila and improves survival of C9ORF72 iPSC-derived motor neurons. These results suggest potential novel therapeutic targets for C9ORF72-ALS/FTD. [Display omitted] •Many antimicrobial peptides and heat shock proteins are activated in poly(GR) flies•Knockdown of Mtk partially rescues poly(GR)-induced toxicity in Drosophila neurons•Hsp90 knockdown suppresses poly(GR) toxicity in flies and death of patient neurons•Hsp90 and Mtk are regulated by TopoII, another suppressor of poly(GR) toxicity Using fruit flies and neurons derived from stem cells of patients with ALS/FTD as their experimental systems, Lee et al. found that the knockdown of three proteins that likely function in a related pathway partially suppresses the neurotoxicity of poly(GR), a pathological protein in ALS/FTD.