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

Abstract

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.

Drosophilaappear resistant to trans-synaptic tau propagation

“…In addition, the resistance to spread seen in this model, compared to mammalian systems, opens up future possibilities to determine factors missing from Drosophila, such as proteins, cell types or neuronal functionality 61,62 that could provide insight into mammalian mechanisms. This also contrasts with fly models successfully showing spread and seeding of toxic neuropathological proteins such as huntingtin [63][64][65] , FUS 66 , TDP-43 67 , and Aβ 68 .…”

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

“…We have previously demonstrated that in Drosophila , pan-glial over-expression of TDP-43 causes loss of nuclear localization and accumulation of cytoplasmic hyperphosphorylated TDP-43 [ 20 , 42 ]. Such pan-glial TDP-43 toxicity reduces lifespan and causes non-cell autonomous toxicity to neurons that appears to involve some combination of astrocytes, PNG and SPG [ 37 , 42 ].…”

“…We have previously demonstrated that in Drosophila , pan-glial over-expression of TDP-43 causes loss of nuclear localization and accumulation of cytoplasmic hyperphosphorylated TDP-43 [ 20 , 42 ]. Such pan-glial TDP-43 toxicity reduces lifespan and causes non-cell autonomous toxicity to neurons that appears to involve some combination of astrocytes, PNG and SPG [ 37 , 42 ]. Importantly, the toxicity to neurons from glial-specific TDP-43 over-expression in a humanized Drosophila model also triggers pathological cytoplasmic accumulation of TDP-43 in nearby neurons where TDP-43 is not over-expressed [ 42 ].…”

Inclusion body myositis, viral infections, and TDP-43: a narrative review

“…Also, the aging cellular environment may make the myofiber susceptible to a newly invading virus, or may allow cytopathic manifestation of a virus, or a vertically transmitted genomic endogenous virus such as a retrovirus dormant for years, such as HTLV1, may start to be transcribed due to the age-modified milieu [ 16 ]. Endogenous retroviruses (ERVs, genomic remnants of ancient viral infections, most inactive and non-infectious) are mutually reinforcing with TDP-43 proteinopathies regarding neurodegeneration [ 17 , 26 ]. Moreover, aging may favor both ERVs expression and TDP-43 proteinopathy [ 26 ].…”

“…Endogenous retroviruses (ERVs, genomic remnants of ancient viral infections, most inactive and non-infectious) are mutually reinforcing with TDP-43 proteinopathies regarding neurodegeneration [ 17 , 26 ]. Moreover, aging may favor both ERVs expression and TDP-43 proteinopathy [ 26 ].…”