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Open Access 01-06-2024 | Amyotrophic Lateral Sclerosis | Original Paper

Neuronal STING activation in amyotrophic lateral sclerosis and frontotemporal dementia

Authors: Christine Marques, Aaron Held, Katherine Dorfman, Joon Sung, Catherine Song, Amey S. Kavuturu, Corey Aguilar, Tommaso Russo, Derek H. Oakley, Mark W. Albers, Bradley T. Hyman, Leonard Petrucelli, Clotilde Lagier-Tourenne, Brian J. Wainger

Published in: Acta Neuropathologica | Issue 1/2024

Abstract

The stimulator of interferon genes (STING) pathway has been implicated in neurodegenerative diseases, including Parkinson’s disease and amyotrophic lateral sclerosis (ALS). While prior studies have focused on STING within immune cells, little is known about STING within neurons. Here, we document neuronal activation of the STING pathway in human postmortem cortical and spinal motor neurons from individuals affected by familial or sporadic ALS. This process takes place selectively in the most vulnerable cortical and spinal motor neurons but not in neurons that are less affected by the disease. Concordant STING activation in layer V cortical motor neurons occurs in a mouse model of C9orf72 repeat-associated ALS and frontotemporal dementia (FTD). To establish that STING activation occurs in a neuron-autonomous manner, we demonstrate the integrity of the STING signaling pathway, including both upstream activators and downstream innate immune response effectors, in dissociated mouse cortical neurons and neurons derived from control human induced pluripotent stem cells (iPSCs). Human iPSC-derived neurons harboring different familial ALS-causing mutations exhibit increased STING signaling with DNA damage as a main driver. The elevated downstream inflammatory markers present in ALS iPSC-derived neurons can be suppressed with a STING inhibitor. Our results reveal an immunophenotype that consists of innate immune signaling driven by the STING pathway and occurs specifically within vulnerable neurons in ALS/FTD.

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Title: Neuronal STING activation in amyotrophic lateral sclerosis and frontotemporal dementia
Authors: Christine Marques
Aaron Held
Katherine Dorfman
Joon Sung
Catherine Song
Amey S. Kavuturu
Corey Aguilar
Tommaso Russo
Derek H. Oakley
Mark W. Albers
Bradley T. Hyman
Leonard Petrucelli
Clotilde Lagier-Tourenne
Brian J. Wainger
Publication date: 01-06-2024
Publisher: Springer Berlin Heidelberg
Keywords: Amyotrophic Lateral Sclerosis
Frontotemporal Dementia
Frontotemporal Dementia
Published in: Acta Neuropathologica / Issue 1/2024
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-024-02688-z

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Neuronal STING activation in amyotrophic lateral sclerosis and frontotemporal dementia

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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