# Retrograde transmission of pathogenic TDP-43 to the CNS > **NIH NIH F32** · WASHINGTON UNIVERSITY · 2024 · $71,741 ## Abstract Project Summary/Abstract TDP-43 is a common protein found aggregated in multiple neurodegenerative diseases and myopathies. TDP- 43 is a ubiquitously expressed RNA-binding protein that is primarily localized in the nucleus but relocates to the cytoplasm under conditions of cellular stress, forming stress granules in neurons and myo-granules in skeletal muscle. Normally TDP-43 returns to the nucleus when the stress is resolved, but through unknown disease mechanisms misfolded TDP-43 remains in the cytoplasm as phosphorylated insoluble aggregates. Studies have shown that TDP-43 forms amyloid-like oligomers which are capable of self-templated conversion in which the misfolded protein causes its native counterpart to become misfolded, leading to propagation of the aggregate pathology. The misfolded aggregation-prone proteins, referred to as proteopathic seeds, are capable of cell-to-cell transmission through connected neuronal networks. In some diseases such as multisystem proteinopathy, patients have TDP-43 aggregation in both skeletal muscle and neurons. In these cases, myopathy symptoms begin several years prior to the onset of dementia. Therefore, the central hypothesis behind this proposal is that TDP-43 is capable of self-templated conversion in skeletal muscle and transmission to the central nervous system (CNS) to cause neurodegeneration. In order to test this, TDP-43 isolated from human skeletal muscle myo-granules will first be tested for the ability to undergo self-templated conversion in vitro using a thioflavin assay and a TDP-43 FRET sensor line. Then, the isolated TDP-43 or recombinant TDP-43 seeds will be injected into the hindlimb muscles of wild type mice and mice expressing TDP-43 with a mutated nuclear localization signal which causes increased cytoplasmic TDP- 43 expression. Mice will be monitored for motor or cognitive changes and sacrificed at specific time points following proteopathic seed injection. Skeletal muscle will be examined for signs of local transmission and pathology to confirm whether seeds can propagate in the environment of a myofiber. Additionally, the spinal cord and brain will be examined for signs of TDP-43 pathology to determine whether intramuscular injected TDP-43 proteopathic seeds can lead to transmission of TDP-43 proteinopathy to the CNS. To confirm muscle- to-neuron transmission of TDP-43 seeds on a shorter timeline, primary mouse myoblasts expressing fluorescently-tagged TDP-43 will be treated with proteopathic seeds and then co-cultured with primary mouse neurons. The neurons will be monitored for fluorescent TDP-43, indicating seeding. If successful, the proposed experiments will significantly improve the understanding of TDP-43 proteinopathy and whether it can spread from the periphery to the CNS. This has the potential to greatly impact the diagnosis methods and treatment options for neurodegenerative diseases. The successful completion of these aims as well as the training plan provided will pr... ## Key facts - **NIH application ID:** 10747401 - **Project number:** 5F32NS124841-03 - **Recipient organization:** WASHINGTON UNIVERSITY - **Principal Investigator:** Eileen Marie Lynch - **Activity code:** F32 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $71,741 - **Award type:** 5 - **Project period:** 2021-12-01 → 2024-10-07 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10747401 ## Citation > US National Institutes of Health, RePORTER application 10747401, Retrograde transmission of pathogenic TDP-43 to the CNS (5F32NS124841-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10747401. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*