Reactivated endogenous retroviruses promote protein aggregate spreading

Abstract

Prion-like spreading of protein misfolding is a characteristic of neurodegenerative diseases, but the exact mechanisms of intercellular protein aggregate dissemination remain unresolved. Evidence accumulates that endogenous retroviruses, remnants of viral germline infections that are normally epigenetically silenced, become upregulated in neurodegenerative diseases such as amyotrophic lateral sclerosis and tauopathies. Here we uncover that activation of endogenous retroviruses affects prion-like spreading of proteopathic seeds. We show that upregulation of endogenous retroviruses drastically increases the dissemination of protein aggregates between cells in culture, a process that can be inhibited by targeting the viral envelope protein or viral protein processing. Human endogenous retrovirus envelopes of four different clades also elevate intercellular spreading of proteopathic seeds, including pathological Tau. Our data support a role of endogenous retroviruses in protein misfolding diseases and suggest that antiviral drugs could represent promising candidates for inhibiting protein aggregate spreading.

TDP-43 pathology in Drosophila induces glial-cell type specific toxicity that can be ameliorated by knock-down of SF2/SRSF1

“…We have previously shown in the context of this Drosophila model that TDP-43 pathology drives expression of the mdg4-ERV, and that mdg4 contributes to the non-cell autonomous effects on neuronal survival [ 37 , 42 ]. Indeed, there is evidence that intercellular movement of ERV generated viral particles may underlie the propagation of toxicity from cell-to-cell [ 67 ]. But it is not at all clear whether different mechanisms underlie inter-cellular signaling effects among each glial and neuronal cell type.…”

Species-Specific Transcription Factors Associated with Long Terminal Repeat Promoters of Endogenous Retroviruses: A Comprehensive Review

“…Misfolded TDP-43 is aggregated and transmitted in patients with ALS [ 162 ]. Interestingly, prion-like proteins (e.g., yeast Sup35 prion NM domain and Tau microtubule-binding domain) are transmitted by ERVs such as HERV-K and HERV-W [ 70 ]. Thus, if ERVs form particles and become active in other cells by transmitting TFs listed in Table 1 , including TDP-43, they may be involved in diseases such as ALS.…”

“…Consequently, they function as ancillaries in processes that aid the progression of diseases, such as oncogenesis, and cellular senescence. Moreover, it may trigger diseases such as autoimmune diseases and neurological disorders [ 66 , 67 , 68 , 69 , 70 ] ( Figure 1 C).…”

Does the interplay between human endogenous retrovirus K and extracellular vesicles contribute to aging?

“…Further, this phenomenon has also been observed in the placenta [ 28 , 32 ] . Extracellular vesicles containing endogenous retroviral nucleic acids and proteins have been implicated in the pathogenesis of various conditions, particularly in age-related diseases [ 4 , 27 ] . Furthermore, a recent publication revealed the reactivation of endogenous retroviral expression could act as a biomarker and even a driver of aging using multiple cross-species models of premature aging phenotypes [ 4 ] .…”

“…In AD, a significant increase in endogenous retrovirus expression was observed and associated with heterochromatin decondensation and depletion of piwi and piRNAs, which normally act to silence their expression [ 58 ] . In a recent study, extracellular vesicles containing either HERV-K HML-2 Env or HERV-W Env (Syncytin-1) were shown to increase protein aggregates in vitro, suggesting their expression in diseases like AD could contribute to Tau aggregation [ 27 ] . These findings suggest that the presence of endogenous retroviral envelope proteins could be used as a biomarker for several age-related neurodegenerative diseases, and this should be further explored in studies with larger numbers of individuals.…”