Human Endogenous Retrovirus K Envelope in Spinal Fluid of Amyotrophic Lateral Sclerosis Is Toxic

Abstract

Objective: Human endogenous retroviruses have been implicated in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Expression of human endogenous retrovirus K (HERV-K) subtype HML-2 envelope (Env) in human neuronal cultures and in transgenic mice results in neurotoxicity and neurodegeneration, and mice expressing HML-2 Env display behavioral and neuromuscular characteristics resembling ALS. This study aims to characterize the neurotoxic properties of HML-2 Env. Methods: Env neurotoxicity was detected in ALS cerebrospinal fluid and confirmed using recombinant Env protein in a cell-based assay and a mouse model. The mechanism of neurotoxicity was assessed with immunoprecipitation followed by mass spectrometry and Western blot, and by screening a panel of inhibitors. Results: We observed that recombinant HML-2 Env protein caused neurotoxicity resulting in neuronal cell death, retraction of neurites, and decreased neuronal electrical activity. Injection of the Env protein into the brains of mice also resulted in neuronal cell death. HML-2 Env protein was also found in the cerebrospinal fluid of patients with sporadic ALS. The neurotoxic properties of the Env and the cerebrospinal fluid could be rescued with the anti-Env antibody. The Env was found to bind to CD98HC complexed to β1 integrin on the neuronal cell surface. Using a panel of compounds to screen for their ability to block Env-induced neurotoxicity, we found that several compounds were protective and are linked to the β1 integrin pathway. Interpretation: HERV-K Env is released extracellularly in ALS and causes neurotoxicity via a novel mechanism. Present results pave the way for new treatment strategies in sporadic ALS.

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

“…It will therefore be important to investigate whether LINE-1 expression also can trigger TDP-43 pathology. Finally, a body of literature has established that RTEs and ERVs become inappropriately expressed not only in TDP-43 related disorders ALS and FTD [12][13][14][15][16][17][18][19][20][21]56,57 , but also in some disorders with Tau pathology (AD and Progressive supranuclear palsy) 58,59 and in Aicardi-Goutieres syndrome 60,61 . RTE and ERV expression has the potential to contribute to many of the cellular impacts that are thought to be at play across these disorders, including inflammatory signaling, DNA damage and defects in RNA metabolism and proteostasis [62][63][64][65] .…”

Antibody Response to HML‐2 May Be Protective in Amyotrophic Lateral Sclerosis

“…Preincubation with a HERV‐W env monoclonal antibody reduced the nitrosative stress induced by HERV‐W env in oligodendrocytes and rescued myelin expression 42 . A pre‐clinical study conducted by our group to explore the therapeutic use of an HML‐2 env monoclonal antibody in ALS has shown the antibody can protect against neurodegeneration caused by HML‐2 env protein both in vitro and in vivo 43, 44 . Moreover, antibodies against HML‐2 env have been found to positively correlate with antibodies against TDP‐43 in ALS individuals 19 .…”

“… 42 A pre‐clinical study conducted by our group to explore the therapeutic use of an HML‐2 env monoclonal antibody in ALS has shown the antibody can protect against neurodegeneration caused by HML‐2 env protein both in vitro and in vivo. 43 , 44 Moreover, antibodies against HML‐2 env have been found to positively correlate with antibodies against TDP‐43 in ALS individuals. 19 An intrabody developed against TDP‐43 has been shown to reduce cytoplasmic aggregation of TDP‐43 in an in vitro model of ALS.…”

HERV-K Envelope Protein Induces Long-Lasting Production of Autoantibodies in T1DM Patients at Onset in Comparison to ZNT8 Autoantibodies

“…It is possible that these proteins could induce the overproduction of anti-HERVs antibodies by B lymphocytes with a protective role, as observed in ALS recently [ 26 ]. Several studies observed the detection of HERV-K Env in the cerebrospinal fluid (CSF) and brain in amyotrophic lateral sclerosis (ALS) patients, noting its specific neurotoxic effect in vitro and in vivo [ 27 , 28 , 29 ]. Significantly increased levels of Abs targeting HERV-K Env in ALS patients were initially reported by our group [ 26 , 30 ].…”