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

Elena Rita Simula,Leonardo A Sechi,Paolo Solla,Ignazio Roberto Zarbo,Giannina Arru

doi:10.3390/v13112301

Elena Rita Simula, Leonardo A Sechi + Show 3 more

Open Access

https://doi.org/10.3390/v13112301

Copy DOI

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.

Highlights

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of unknown etiology described for the first time in 1874 by Jean-Martin Charcot
The humoral response against human endogenous retrovirus-K (HERV-K)-env-su(20–38) and three selected epitopes of TAR DNA-binding protein 43 (TDP-43) was evaluated in the plasma of the amyotrophic lateral sclerosis (ALS) and healthy controls (HCs) groups
The ALS patients showed an increased Abs presence against the TDP-43(398–411) epitope (Figure 1C), with a positivity measured in 51.11% of the ALS group versus 4.44% of HCs with a Fisher’s exact test p < 0.0001 (Mann–Whitney U test, p < 0.0001, HCs median = 0.11, 95% CI [0.074, 0.168], ALS median = 0.386, 95% CI [0.332, 0.453]; cut off value of 0.385; and AUC = 0.915)

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of unknown etiology described for the first time in 1874 by Jean-Martin Charcot. It is characterized by the progressive degeneration of both the upper and lower motor neurons, which display cytoplasmatic inclusions [1,2]. Population-based studies have highlighted that women are less affected by sporadic ALS (sALS) than men, while the same incidence between men and women in familial ALS (fALS) is observed. The incidence decreases rapidly after 80 years of age, whereas the 58–63 and 47-52 age brackets represent the peak ages of onset for sALS and fALS, respectively [3]. There are several hypotheses behind the development of the disease, involving both genetic predisposition, with more than 24 implicated genes, such as Superoxide dismutase 1 (SOD1) and TAR DNA-binding protein 43 (TDP-43) [6], and environmental risk factors, for instance, smoking [7], physical activity [8], and chemical exposure [9,10]

Objectives

Methods

Results

Discussion

Conclusion