Pro-Inflammatory Signaling Upregulates a Neurotoxic Conotoxin-Like Protein Encrypted Within Human Endogenous Retrovirus-K.

Domenico Di Curzio,Breanna Meek,Matthew Turnbull,Jennifer Ferguson-Parry,Samuel Fineblit,Sherry Hebert,Julia D Rempel,Marie-Josée Nadeau,Mamneet Gurm,Renée N Douville,Michael Jonasson

doi:10.3390/cells9071584

Domenico Di Curzio, Breanna Meek + Show 9 more

Open Access

https://doi.org/10.3390/cells9071584

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Journal: Cells	Publication Date: Jun 30, 2020
Citations: 21	License type: CC BY 4.0

Affiliation: University of Winnipeg, University of Manitoba

Abstract

Motor neuron degeneration and spinal cord demyelination are hallmark pathological events in Amyotrophic Lateral Sclerosis (ALS). Endogenous retrovirus-K (ERVK) expression has an established association with ALS neuropathology, with murine modeling pointing to a role for the ERVK envelope (env) gene in disease processes. Here, we describe a novel viral protein cryptically encoded within the ERVK env transcript, which resembles two distinct cysteine-rich neurotoxic proteins: conotoxin proteins found in marine snails and the Human Immunodeficiency Virus (HIV) Tat protein. Consistent with Nuclear factor-kappa B (NF-κB)-induced retrotransposon expression, the ERVK conotoxin-like protein (CTXLP) is induced by inflammatory signaling. CTXLP is found in the nucleus, impacting innate immune gene expression and NF-κB p65 activity. Using human autopsy specimens from patients with ALS, we further showcase CTXLP expression in degenerating motor cortex and spinal cord tissues, concomitant with inflammation linked pathways, including enhancement of necroptosis marker mixed lineage kinase domain-like (MLKL) protein and oligodendrocyte maturation/myelination inhibitor Nogo-A. These findings identify CTXLP as a novel ERVK protein product, which may act as an effector in ALS neuropathology.

Highlights

Viruses and toxins are considered potential environmental factors implicated in the motor neuron disease Amyotrophic Lateral Sclerosis (ALS) [1,2,3]
Protein product termed conotoxin-like protein (CTXLP), which is cryptically encoded within Endogenous retrovirus-K (ERVK) env and may help elucidate the neuropathological nature of ERVK reactivation
While the concert of pathological pathways underlying the inception and progression of motor neuron death in ALS is complex, here we focus on the connection between ERVK CTXLP and neuropathological events in ALS, such as inflammation [42], proteinopathy [43], necroptosis [44], and oligodendrocyte perturbation [45,46]

Summary

Introduction

Viruses and toxins are considered potential environmental factors implicated in the motor neuron disease Amyotrophic Lateral Sclerosis (ALS) [1,2,3]. With most ALS cases considered sporadic in nature, the search for gene-environment interactions in ALS has remained disappointingly elusive [4,5]. Endogenous retrovirus-K (ERVK) expression has been repeatedly associated with. ALS neuropathology [6,7,8,9], with murine modeling pointing to a role for the ERVK envelope (env) gene as a cause of motor neuron loss [10]. Recent studies conflict with previous findings by suggesting there is no significant difference in ERVK env transcripts and protein expression between. The role of ERVK env in disease remains

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