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Cadoni, M.P.L.; Biggio, M.L.; Arru, G.; Secchi, G.; Orrù, N.; Clemente, M.G.; Sechi, G.; Yamoah, A.; Tripathi, P.; Orrù, S.; et al. HERV-K Modulates the Immune Response in ALS Patients. Encyclopedia. Available online: (accessed on 15 June 2024).
Cadoni MPL, Biggio ML, Arru G, Secchi G, Orrù N, Clemente MG, et al. HERV-K Modulates the Immune Response in ALS Patients. Encyclopedia. Available at: Accessed June 15, 2024.
Cadoni, Maria Piera L, Maria Luigia Biggio, Giannina Arru, Giannina Secchi, Nicola Orrù, Maria Grazia Clemente, Gianpietro Sechi, Alfred Yamoah, Priyanka Tripathi, Sandro Orrù, et al. "HERV-K Modulates the Immune Response in ALS Patients" Encyclopedia, (accessed June 15, 2024).
Cadoni, M.P.L., Biggio, M.L., Arru, G., Secchi, G., Orrù, N., Clemente, M.G., Sechi, G., Yamoah, A., Tripathi, P., Orrù, S., Manetti, R., & Galleri, G. (2023, July 07). HERV-K Modulates the Immune Response in ALS Patients. In Encyclopedia.
Cadoni, Maria Piera L, et al. "HERV-K Modulates the Immune Response in ALS Patients." Encyclopedia. Web. 07 July, 2023.
HERV-K Modulates the Immune Response in ALS Patients

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects both lower motor neurons in brainstem and spinal cord and upper motor neurons in motor cortex. 

amyotrophic lateral sclerosis HERV-K

1. Background

Amyotrophic lateral sclerosis (ALS) pathogenesis is poorly understood, and currently, there is neither a cure nor a specific diagnostic test for this disease. Approximately 90% of ALS cases are sporadic (sALS), while the remaining 10% of cases are familial (fALS) [1][2]. Several genes involved in ALS pathomechanisms have been identified [3][4][5], and all of these can cause motor neurons death through different mechanisms such as oxidative stress, mitochondrial dysfunctions, protein aggregates formation, glutamate toxicity, and neuroinflammation [5][6][7][8]. Among ALS-causative genes, a point mutation, proline to serine substitution at position 56 (P56S), in a vesicle-associated membrane-protein-associated protein B (VAPB)-encoding gene, responsible for a rare fALS case and classified as ALS-8 [9], has been identified, which is associated with a highly variable clinical course [10]. VAPB belongs to the family of vesicle-associated membrane-protein-associated proteins, endoplasmic reticulum (ER) resident proteins [11][12], which play different roles in cells for regulation of calcium homeostasis, vesicle trafficking, bouton formation at a neuromuscular junction, microtubules organization, lipid transport, and unfolded protein response (UPR) [12][13][14][15]. The most frequent mutation in VAPB-encoding genes is P56S [9]. However, other more rare mutations have been identified [10]. The presence of VAPB mutant genes causes an impairment of the protein, resulting in intracellular protein inclusions, already characterized in transgenic mice [9], which entails an abnormal reorganization of an ER structure and alters cellular homeostasis [9][11][13][16][17][18][19][20]. Several studies in human and transgenic mice have documented that VAPB inclusions also occur when other ALS-causative genes are present, such as superoxide dismutase 1 (SOD1) [21], TAR DNA-binding protein (TDP43) [22], and chromosome 9 open reading frame 72 (C9orf72) repeat expansion [23]. Moreover, there are evidences that suggest VAPB involvement in sALS [9][13][20]. In the present paper, researchers studied VAPB as a possible ALS pathologic marker by analyzing peripheral blood mononuclear cells (PBMCs) isolated from sALS-affected patients. In fact, PBMCs share more than 80% of their transcriptomes with other tissues, including the central nervous system, and can be isolated easily from patients by venipuncture [24]. Previous studies demonstrated that PBMCs are a valid cell model to study ALS [24][25][26][27]. Based on this and on the new vision of ALS as a pathology affecting not only motor neurons exclusively but also other cell systems [28][29][30], researchers investigated the possible role of VAPB as a pathologic marker in PBMCs from patients with sALS.

2. Cellular Model Analysis

In HeLa cells stained by IFA with an antihuman VAPB polyclonal antibody, VAPB ER-aggregates were present in those transfected with mutant VAPB (P56S), but not in VAPB-Wt HeLa cells (Figure 1a). As others have shown, these aggregates are caused by VAPB misfolding [11][14][16][19] that lead to ER reorganization [9][11][31]. Performing the FCA with the antihuman VAPB monoclonal antibody, researchers observed a reduction in VAPB fluorescent signal in VAPB-P56S-transfected HeLa cells compared to in VAPB-Wt Hela cells (p = 0.0003). This evidence revealed that, in presence of VAPB misfolding, the monoclonal antibody lost the ability to bind efficiently its recognition site to the protein, causing a reduction of fluorescent signal detection (Figure 1b). The western blot analysis confirmed the data reported in the literature. In fact, as expected, VAPB-P56S cells showed increased levels of GRP-78, HSP-70, P62 LC3 I and II, and ubiquitin (Figure 1c,d), all cellular stress markers that are overexpressed in presence of misfolded protein accumulation [32][33][34][35][36][37][38].
Figure 1. Representative immunofluorescence images performed with an antihuman VAPB polyclonal antibody in Hela cell lines. (a) VAPB (green) and nuclei (blue) in HeLa cells transfected with VAPB-Wt (left) and VAPB-P56S (right). Magnification is the same in both pictures (scale bar: 15 µm). The image shows VAPB aggregates and ER disorganization in VAPB-P56S-transfected HeLa cells caused by VAPB misfolding. (b) FCAs performed with an antihuman VAPB monoclonal antibody. The data, expressed as medium intensities of fluorescence (MFIs), show a statistically significant reduction of fluorescence signals in VAPB-P56S-transfected HeLa cells compared to in VAPB-Wt-transfected HeLa cells. (c) Representative western blot analysis showing the expression of GRP78, p62, and LC3 proteins and ubiquitin protein in VAPB-Wt- and VAPB-P56S-transfected cells. β-tubulin was used as a loading control. For each analysis, around 15 µg of protein were loaded. All western blot experiments were performed in triplicate. (d) Quantification of band intensities normalized with a β-tubulin value depicted in (c). Densitometry analysis was performed using the software ImageJ. Data are from one representative experiment out of three. *** p < 0.0005.

3.  Vesicle-Associated Membrane-Protein-Associated Protein B ER-Aggregates in Sporadic Amyotrophic Lateral Sclerosis Patients Peripheral Blood Mononuclear Cells 

The pattern of VAPB immunofluorescence was substantially different in PBMCs from sALS patients compared to those obtained from patients with PD and HCs (Figure 2). The stain with an antihuman VAPB polyclonal antibody revealed a uniform signal in HCs (Figure 2a–c) and patients with PD (Figure 2d–f) PBMC cytoplasm, while fluorescence patterns in all the sALS patients PBMCs were characterized by numerous VAPB clusters distributed around the nucleus (Figure 2g–i). These VAPB aggregates were similar to the staining pattern of mutant VAPB-P56S overexpressed in HeLa cells (Figure 1a) and might be a representative of defective ER organization [2][9][11][19] caused by VAPB misfolding. An average of 70% of total PBMCs carrying ER-aggregates analyzed were observed in sALS subjects compared to an average of 2% in PD patients (p < 0.00001) and 0% in HCs (p < 0.00001). The monoclonal antibody showed a similar pattern compared to the polyclonal antibody, but its signals were basically weaker in HCs and PD patients and were basically negative in all the sALS (data not shown).
Figure 2. Representative confocal monochromatic nucleus (a,d,g), VAPB (b,e,h), and merge (c,f,i) images of immunofluorescence performed with an antihuman VAPB polyclonal antibody in PBMCs of HCs, PD patients, and sALS patients. VAPB is represented in green, and the nuclei are in blue. (i) The merge image shows the presence of VAPB ER-aggregates in sALS patients that is clearly different from those obtained in PD patients (f) and HCs (c). The arrows indicate VAPB ER-aggregates. Scale bars: 20 µm. Each sample were analyzed in 20 fields. For each subject, the number of lymphocytes showing VAPB aggregates was divided by the original total number of isolated cells (2 × 104).

4. Vesicle-Associated Membrane-Protein-Associated Protein B Accumulations in Sporadic Amyotrophic Lateral Sclerosis Patients Fibroblasts

Prompted by the observation of VAPB accumulations in PBMCs of the sALS patients, researchers asked if researchers could detect similar early changes of VAPB in fibroblasts obtained from skin biopsy of sALS patients. Applying the same antihuman VAPB polyclonal antibody on the sALS and healthy donor fibrosblasts, researchers observed, in sALS, a globular accumulation of VAPB (Figure 3a), which were consistent with the data obtained from PBMC analysis. VAPB aggregates were colocalized with GRP78, a trasmembrane protein of ER (Figure 3b), confirming that these aggregates are strongly associated to this cellular organel.
Figure 3. (a) Representative immunofluorescence image of primary skin fibroblasts performed with an antihuman VAPB polyclonal antibody. VAPB (green) and nuclei (blue) in fibroblasts were isolated from HCs (left) and sALS patients (right). The sALS patient fibroblasts staining showed globular accumulations of VAPB (indicated by arrows) compared to the control. (b) Image showing single staining of VAPB (green) (left), GRP78 (red) (middle), and merge (right). The merge evidenced the colocalization of GRP-78 with the VAPB accumulations (indicated by arrows) representing the ER distribution. Scale bars: 15 µm.

5. Decrease of Vesicle-Associated Membrane-Protein-Associated Protein B Fluorescent Signals in Sporadic Amyotrophic Lateral Sclerosis Patients

The findings of VAPB aggregates in PBMCs and fibroblasts from sALS patients obtained by IFA prompted researchers to suppose that VAPB could be misfolded in sALS. Therefore, researchers quantified, by an FCA, fluorescent signals of VAPB protein using antihuman VAPB polyclonal and monoclonal antibodies. The data obtained by a monoclonal antibody assay confirmed indirectly researchers' hypothesis of VAPB misfolding. In fact, researchers revealed a statistically significant reduction of VAPB fluorescent signals (MFI) in sALS compared to in HCs with a p-value of 0.018 and PD controls with a p-value of 0.003 (Figure 4). This result revealed a reduced ability of the monoclonal antibody to bind its recognition site only in sALS, supposing that this protein site was misfolded or hidden. On the contrary, the same analysis performed with the polyclonal antibody did not reveal significant differences of VAPB fluorescent signals between patients with sALS and PD and HCs, most likely due to the fact that the polyclonal antibody recognized more VAPB epitopes than the monoclonal antibody.
Figure 4. FCAs performed with a monoclonal antibody against VAPB. The graph shows a statistically significant decreased level of VAPB fluorescence detection in sALS patients compared to in PD patients and HCs. On the contrary, VAPB fluorescence signals in HCs and PD patients did not present significant differences. The data are expressed as MFIs in all patients and controls analyzed. * p < 0.05; ** p < 0.005.

6. Nonalteration of Vesicle-Associated Membrane-Protein-Associated Protein B mRNA Expression in Sporadic Amyotrophic Lateral Sclerosis Patients

On the basis of the results obtained by cytometric analysis, researchers decided to quantify VAPB gene expression by real-time PCR. In the current literature about VAPB expression, some authors declare that both VAPB and VAPA are reduced in human ALS patients and SOD1 ALS transgenic mice, suggesting that VAP family proteins may be involved in the pathogenesis of sporadic and SOD1-linked ALS [11]. However, the data obtained revealed the expression of VAPB mRNA in sALS patients (n = 24; mean ± SD: 0.055 ± 0.031), which was not significantly different from that in HCs (n = 24; mean ± SD: 0.033 ± 0.0105; p = 0.1423) (Figure 5).
Figure 5. VAPB mRNA expression in PBMCs from HCs (n = 24) and ALS (n = 24) patients. mRNA levels were quantified by real-time PCR. mRNA values are normalized by that of GAPDH. Values represent mean ± SD. Each sample was examined in triplicate. VAPB mRNA levels of sALS patients were not significantly different from those detected in HCs.

7. Western Blot Analysis of Peripheral Blood Mononuclear Cells

The western blot analysis performed with proteins preparation obtained from PBMCs of sALS patients, PD patients, and HCs showed, as expected, ubiquitin conjugates overexpression in sALS and PD patients compared to in HCs. This results are consistent with accumulation of ubiquitinated proteins in PBMC cytoplasm of ALS and PD [33][38]. HSP90 also was overexpressed in PD controls and sALS patients but not in HCs (Figure 6a,b).
Figure 6. (a) Representative western blot data from one HC and two PD- and two sALS-affected patients. The image shows the overexpression of ubiquitin and HSP90 in sALS and PD patients compared to in the HCs. For each analysis, around 15 µg of protein were loaded. β-tubulin was used as a loading control. (b) Quantification of band intensities normalized with a β-tubulin value depicted in (a). Densitometry analysis was performed using the software Image. All western blot experiments were performed in triplicate. *** p < 0.0005.

8. Genetic Analysis

The genetic analysis by NGS assays was performed to evaluate if VAPB clusters observed by IFA could be caused by VAPB gene mutation. Moreover, to best characterize series of patients, researchers checked also for the presence of genetic mutation in the major ALS-related genes (SOD-1, TARDPB, FUS, and C9orf72). The data obtained revealed the presence of the A382T mutation of the TARDBP gene in three patients and pathogenic expansion in the C9orf72 gene in one patient. The 20 remaining patients analyzed did not reveal the presence of mutation in any of the genes analyzed, with the VAPB gene included.


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