Endogenous Retroviruses and TDP-43 Proteinopathy Form a Sustaining Feedback to Drive the Intercellular Spread of Neurodegeneration

Abstract

Neurodegenerative disorders are thought to initiate focally and then spread over time through neural circuits. A mechanism that has been proposed to explain this is the inter-cellular movement of misfolded “prion-like” proteins that then recruit normally folded proteins in recipient cells to also adopt pathological conformations. Such a mechanism has been proposed, for example, to explain the propagation of abnormally phosphorylated cytoplasmic inclusions of TAR-DNA-Binding protein (TDP-43) during the progression of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). But unlike transmissible prion diseases such as mad cow disease, which can be caused by ingestion or by injection into animal brains of misfolded PrP, ALS and FTD are not infectious and the injection of phosphorylated and aggregated TDP-43 protein into rodent brains is not sufficient to cause disease phenotypes unless those animals also express high levels of transgenic TDP-43 protein. This suggests a missing component of a positive feedback that is necessary to sustain disease progression. We provide evidence that endogenous retroviruses (ERVs) are that missing component. We demonstrate that ERV expression and TDP-43 proteinopathy are mutually reinforcing. Expression of either the Drosophila ERV, gypsy (mdg4) or the human ERV, HERV-K (HML-2) are each sufficient to stimulate cytoplasmic aggregation of human TDP-43. Importantly. We also demonstrate that viral ERV transmission causes propagation of such TDP-43 pathology to cells that express physiological levels of TDP-43, whether they are in contact or at a distance. This mechanism underlies the toxicity of glial cells to neurons and other glia in a Drosophila in vivo model.

Single-cell transcriptomics of resected human traumatic brain injury tissues reveals acute activation of endogenous retroviruses in oligodendroglia

“…In addition, ERV-derived peptides may contribute to protein aggregation, which may further enhance an inflammatory response 48 . Future mechanistic in-vitro modeling in human oligodendrocyte cultures will be essential to resolve this question.…”

“…The induction of interferon-linked genes has been associated with ERV activation: ERVs are thought to play a part in boosting this response 47 . In addition, ERV-derived peptides may contribute to protein aggregation, which may further enhance an inflammatory response 48 . Future mechanistic in-vitro modeling in human oligodendrocyte cultures will be essential to resolve this question.…”

“…In addition, ERV-derived peptides may contribute to protein aggregation, which may further enhance an inflammatory response 50 .…”