TDP-43 and HERV-K Envelope-Specific Immunogenic Epitopes Are Recognized in ALS Patients

Abstract

The human endogenous retrovirus-K (HERV-K) and TAR DNA-binding protein 43 (TDP-43) have been associated with the pathophysiology of amyotrophic lateral sclerosis (ALS). Given these findings, we investigated the humoral response against HERV-K envelope surface (env-su) glycoprotein antigens and TDP-43 in the plasma of ALS patients and healthy controls (HCs). The measured levels of Abs against the different epitopes' fragments were significantly elevated in ALS patients, both in long-survivor (LS) and newly diagnosed (ND) patients, compared to HCs. We observed a positive correlation between HERV-K and TDP-43 antibodies (Abs) levels, which seemed to strengthen with disease progression, that was not found in HCs. The TDP-43 and HERV-K epitopes identified in this study are highly immunogenic and recognized by the humoral response of ALS patients. Increased circulating levels of Abs directed against specific HERV-K- and TDP-43-derived epitopes could serve as possible biomarkers.

Keywords: ALS; HERV-K; HML-2; TDP-43; amyotrophic lateral sclerosis.

Figure 1

ELISA-based analysis of Abs reactivity against HERV-K- and TDP-43-derived peptides. Plasma samples from ALS patients and HCs subjects were tested against HERV-K-env-su_(20–38) (A), TDP-43_(258–271) (B), TDP-43_(398–411) (C), and TDP-43_(398–411)P (D) peptides. Median and dashed lines represent thresholds used to assess the samples’ positivity. The Mann–Whitney p-value and the percentage of positive patients evaluated by Fisher’s exact test are indicated in the upper part of each graph.

Figure 2

ELISA-based analysis of Abs reactivity against TDP-43- and HERV-K-derived peptides in ALS-ND, ALS-LS, and HCs groups. Plasma samples were tested against HERV-K-env-su_(20–38) (A), TDP-43_(258–271) (B), TDP-43_(398–411) (C), and TDP-43_(398–411)P (D) peptides. A Kruskal–Wallis test and Dunn’s post hoc analysis were performed. Scatter plots represent the median, and the p-value is indicated in the upper part of each graph.

Figure 3

Scatter plots of antibodies to TDP-43, derived peptides, and HERV-K env epitope in ALS populations. The graphs show the correlation between HERV-K-env-su_(20–38) and TDP-43_(258–271), TDP-43_(398–411), and TDP-43_(398–411)P in ALS patients (A,C,E) and in HCs (B,D,F).

Figure 4

Scatter plots of antibodies to TDP-43-derived peptides and HERV-K env epitope in ALS populations. The graphs show the correlation between HERV-K-env-su_(20–38) and TDP-43_(258–271), TDP-43_(398–411), and TDP-43_(398–411)P in ALS-ND patients (A,C,E) and in ALS-LS (B,D,F).