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TDP-43 pathology links innate and adaptive immunity in amyotrophic lateral sclerosis.

Baggio A EvangelistaJoey V RagusaKyle PellegrinoYija WuIvana Yoseli Quiroga-BarberShannon R CahalanOmeed K AroojiJillann A MadrenSally SchroeterJoe CozzarinLing XieXian ChenKristen K WhiteJ Ashley EzzellMarie A IannoneStephanie M CohenRebecca E TraubXiaoyan LiRichard BedlackDouglas H PhanstielRick B MeekerNatalie StanleyTodd J Cohen
Published in: bioRxiv : the preprint server for biology (2024)
Amyotrophic lateral sclerosis is the most common fatal motor neuron disease. Approximately 90% of ALS patients exhibit pathology of the master RNA regulator, Transactive Response DNA Binding protein (TDP-43). Despite the prevalence TDP-43 pathology in ALS motor neurons, recent findings suggest immune dysfunction is a determinant of disease progression in patients. Whether TDP-43 pathology elicits disease-modifying immune responses in ALS remains underexplored. In this study, we demonstrate that TDP-43 pathology is internalized by antigen presenting cells, causes vesicle rupture, and leads to innate and adaptive immune cell activation. Using a multiplex imaging platform, we observed interactions between innate and adaptive immune cells near TDP-43 pathological lesions in ALS brain. We used a mass cytometry-based whole-blood stimulation assay to provide evidence that ALS patient peripheral immune cells exhibit responses to TDP-43 aggregates. Taken together, this study provides a novel link between TDP-43 pathology and ALS immune dysfunction, and further highlights the translational and diagnostic implications of monitoring and manipulating the ALS immune response.
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