and P.S.; writingoriginal draft, E.R.S.; writingreview and editing, L.A.S. circulating levels of Abs directed against specific HERV-K- and TDP-43-derived epitopes could serve as possible biomarkers. transcripts in post-mortem brain samples Flufenamic acid of patients affected by ALS compared to other pathological conditions such as Parkinsons disease, chronic systemic illnesses, and healthy subjects [12]. Transgenic animals, in whose neurons the gene was expressed, developed progressive motor dysfunction [13]. It is noteworthy that HERV-K expression is regulated by TDP-43, which can bind to the long terminal repeat region (LTR) of the virus. Human neurons transfected with TDP-43 showed an increase in HERV-K expression, while knockdown of endogenous TDP-43 resulted in a decrease in HERV-K expression [13]. Furthermore, it was demonstrated that Abs levels against HERV-K-env-su(20C38) were significantly elevated in ALS patients compared to multiple sclerosis (SM), Alzheimers disease (AD), and healthy control subjects, both in serum and cerebrospinal fluid (CSF), suggesting HERV-K-env-su(20C38) as a possible early novel biomarker [14]. Specific post-translational modifications of TDP-43 may have an impact on HERV-K expression patterns. Concerning this, the formation of TDP-43 aggregates alters HERV-K RT, polyprotein levels, and the cellular localization of the viral proteins [15]. Li et al. [13] demonstrated that HERV-K LTR has four binding sites for TDP-43 that have been shown to regulate its activation. In HIV patients an increased nuclear TDP-43 expression accompanied by an enhanced TDP-43 phosphorylation compared to the levels observed in controls has been reported. The co-expression of HERV-K RT and TDP-43 proteins has been observed in the majority of neurons with a significant positive correlation between them [16]. TDP-43 is a multifunctional protein associated with several biological functions [17], including Flufenamic acid mRNA transcription, splicing and stability [18,19,20], stress granule formation [21], and Protein-Protein Interactions [22]. TDP-43 is indispensable for the development of the central nervous system (CNS) from the earliest stages of embryonic life to adulthood [23,24]. Under physiological conditions, TDP-43 is mainly a nuclear protein, but it also shuttles to the cytoplasm for further functions. Neurons transfected with TDP-43 mutants altering nuclear trafficking exhibit cytoplasmic Flufenamic acid aggregates with phosphorylated and ubiquitinated Rabbit polyclonal to ABCB5 TDP-43, which is characteristic of ALS pathology [25]. The TARDBP gene is located on chromosome 1, and the TDP-43 protein consists of 414 amino acids. The C-terminal region, which plays a crucial role in the disease, encompasses a prion-like glutamine/asparagine-rich (Q/N) domain and a glycine-rich region [26]. TDP-43 represents a target for numerous post-translational modifications that may change its structure, functions, localization, and its aggregative predisposition [27,28]. The most documented post-translational modifications in ALS patients are phosphorylation in serine-409 and serine-410 [29,30], but other phosphorylated sites of pathological TDP-43 have also been described, such as serine-379, 403, and 404 [29,31,32]. Kametani et al., showed that all serine and threonine residues in the C-terminal domain can become phosphorylated [33], and this may increase the tendency of TDP-43 to be hydrolyzed into C-terminal fragments or to aggregate [34]. To date, the ALS diagnostic process requires approximately one year, since only the progression of symptoms and the presence of signs of both upper and lower motor neuron involvement can confirm the ALS diagnosis. The diagnosis is based on clinical examination, electrophysiological findings, medical history, and exclusion of confounding disorders [35]. Unfortunately, no effective therapies able to cure the disease are available; Riluzole is the only therapy that can prolong ALS survival (by approximately three months). Different treatments are available to help control ALS symptoms, prevent unnecessary complications, and make it easier for patients to live with the disease. This study aims to more deeply understand the possible relationship between TDP-43 and HERV-K through the investigation of the humoral response to different epitopes of the TDP-43 C-termina region and the HERV-K envelope. The detection of circulating autoantibodies is crucial in the diagnosis and monitoring of several diseases, and it helps to understand the etiopathogenesis. Furthermore, this approach may be useful to hypothesize new biomarkers for ALS which would allow a faster diagnosis. 2. Materials and Methods 2.1. Samples Collection We evaluated an ALS group of 45 patients (17 Flufenamic acid females and 28 males; mean age SD: 64.67 9.11 years), and an age- and gender-matched healthy control group (HCs) collected from the Blood Transfusion Centre of Sassari (17 females and 28 males; mean age SD: 63.87 4.82 years). Data are summarized in Table.
