Person: Frosch, Matthew
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Publication Genomic characterization of brain metastases identifies drivers of metastatic lung adenocarcinoma
(Elsevier BV, 2020-06) Shih, David; Nayyar, Naema; Bihun, Ivanna; Dagogo-Jack, Ibiayi; Gill, Corey; Aquilanti, Elisa; Bertalan, Mia; Kaplan, Alexander; Chukwueke, Ugonma; Ippen, Franziska; Alvarez-Breckenridge, Christopher; Camarda, Nicholas; Lastrapes, Matthew; McCabe, Devin; Kuter, Ben; Kaufmann, Benjamin; Strickland, Matthew; Martinez-Gutierrez, Juan Carlos; Nagabhushan, Deepika; De Sauvage, Magali; White, Michael; Castro, Brandyn; Hoang, Kaitlin; Kaneb, Andrew; Batchelor, Emily; Paek, Sun Ha; Park, Sun Hye; Martinez-Lage Alvarez, Maria; Berghoff, Anna S.; Merrill, Parker; Gerstner, Elizabeth; Batchelor, Tracy; Frosch, Matthew; Frazier, Ryan P.; Borger, Darrell; Iafrate, Anthony; Santagata, Sandro; Preusser, Matthias; Cahill, Daniel; Carter, Scott; Brastianos, PriscillaPublication Genome-Encoded Cytoplasmic Double-Stranded RNAs, Found in C9ORF72 ALS-FTD Brain, Propagate Neuronal Loss
(Science Press / AAAS, 2021-07-07) Rodriguez, Steve; Sahin, Asli; Schrank, Benjamin R.; Al Lawati, Hawra; Costantino, Isabel; Benz, Eric; Fard, Darian; Albers, Alefiya; Cao, Luxiang; Gomez, Alexis; Evans, Kyle; Ratti, Elena; Cudkowicz, Merit; Frosch, Matthew; Talkowski, Michael; Sorger, Peter; Hyman, Bradley; Albers, MarkTriggers of innate immune signaling in the CNS of amyotrophic lateral sclerosis and frontotemporal degeneration (ALS/FTD) patients remain elusive. We report the presence of cytoplasmic double-stranded RNA (cdsRNA), an established trigger of innate immunity, in ALS-FTD brains carrying C9ORF72 intronic hexanucleotide expansions that included genomically encoded expansions of the G4C2 repeat sequences. Presence of cdsRNA in human brains was coincident with cytoplasmic TAR DNA-binding protein 43 (TDP-43) inclusions, a pathologic hallmark of ALS/FTD. Introducing cdsRNA into cultured human neural cells induced Type I interferon (IFN-I) signaling and death that was rescued by FDA-approved JAK inhibitors. In mice, genomically encoded dsRNAs expressed exclusively in a neuronal class induced IFN-I and death in connected neurons non-cell autonomously. Our findings establish that genomically encoded cdsRNAs trigger sterile, viral-mimetic IFN-I induction, and propagated death within neural circuits and may drive neuroinflammation and neurodegeneration in ALS/FTD patients.