Endogenous retroviruses and TDP-43 proteinopathy form a sustaining feedback driving intercellular spread of Drosophila neurodegeneration

• Published in: Nature communications Vol. 14; no. 1; p. 966
• Main Authors: Chang, Yung-Heng, Dubnau, Josh
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.02.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/106; 14; 14/19; 631/378/1689/1285; 631/378/1934; 64; 64/24; 82/1; 82/29; Agglomeration; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Animals; Dementia disorders; DNA-binding protein; DNA-Binding Proteins - metabolism; Drosophila; Drosophila - metabolism; Endogenous retroviruses; Endogenous Retroviruses - metabolism; Feedback; Frontotemporal dementia; Frontotemporal Dementia - genetics; Fruit flies; Humanities and Social Sciences; Humans; Inclusion bodies; Inclusions; Insects; multidisciplinary; Neurodegeneration; Pathology; Positive feedback; Propagation; Protein interaction; Proteins; Science; Science (multidisciplinary); TDP-43 Proteinopathies - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-36649-z

Inter-cellular movement of “prion-like” proteins is thought to explain propagation of neurodegeneration between cells. For example, propagation of abnormally phosphorylated cytoplasmic inclusions of TAR-DNA-Binding protein (TDP-43) is proposed to underlie progression of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). But unlike transmissible prion diseases, ALS and FTD are not infectious and injection of aggregated TDP-43 is not sufficient to cause disease. This suggests a missing component of a positive feedback necessary to sustain disease progression. We demonstrate that endogenous retrovirus (ERV) expression and TDP-43 proteinopathy are mutually reinforcing. Expression of either Drosophila mdg4-ERV (gypsy) or the human ERV, HERV-K (HML-2) are each sufficient to stimulate cytoplasmic aggregation of human TDP-43. Viral ERV transmission also triggers TDP-43 pathology in recipient cells that express physiological levels of TDP-43, whether they are in contact or at a distance. This mechanism potentially underlies the TDP-43 proteinopathy-caused neurodegenerative propagation through neuronal tissue. Expression of Drosophila or human endogenous retroviruses (ERVs) is sufficient to cause TDP-43 protein aggregation, and viral transmission of the ERVs triggers TDP-43 pathology in recipient cells. This mechanism may underly spread of neurodegenerative effects in a Drosophila model.