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 CohenPublished 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.
Keyphrases
- amyotrophic lateral sclerosis
- immune response
- end stage renal disease
- ejection fraction
- newly diagnosed
- chronic kidney disease
- high throughput
- toll like receptor
- dendritic cells
- binding protein
- prognostic factors
- high resolution
- induced apoptosis
- risk factors
- case report
- cell death
- spinal cord
- multiple sclerosis
- cell proliferation
- spinal cord injury
- endoplasmic reticulum stress
- cell cycle arrest
- functional connectivity
- pi k akt
- cell free