Molecular characteristics of Human Endogenous Retrovirus type-W in schizophrenia and bipolar disorder.: HERV-W in schizophrenia and bipolar disorder

International audienceEpidemiological and genome-wide association studies of severe psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BD), suggest complex interactions between multiple genetic elements and environmental factors. The involvement of genetic elements such as Human Endogenous Retroviruses type 'W' family (HERV-W) has consistently been associated with SZ. HERV-W envelope gene (env) is activated by environmental factors and encodes a protein displaying inflammation and neurotoxicity. The present study addressed the molecular characteristics of HERV-W env in SZ and BD. Hundred and thirty-six patients, 91 with BD, 45 with SZ and 73 healthy controls (HC) were included. HERV-W env transcription was found to be elevated in BD (P<10-4) and in SZ (P=0.012) as compared with HC, but with higher values in BD than in SZ group (P<0.01). The corresponding DNA copy number was paradoxically lower in the genome of patients with BD (P=0.0016) or SZ (P<0.0003) than in HC. Differences in nucleotide sequence of HERV-W env were found between patients with SZ and BD as compared with HC, as well as between SZ and BD. The molecular characteristics of HERV-W env also differ from what was observed in Multiple Sclerosis (MS) and may represent distinct features of the genome of patients with BD and SZ. The seroprevalence for Toxoplasma gondii yielded low but significant association with HERV-W transcriptional level in a subgroup of BD and SZ, suggesting a potential role in particular patients. A global hypothesis of mechanisms inducing such major psychoses is discussed, placing HERV-W at the crossroads between environmental, genetic and immunological factors. Thus, particular infections would act as activators of HERV-W elements in earliest life, resulting in the production of an HERV-W envelope protein, which then stimulates pro-inflammatory and neurotoxic cascades. This hypothesis needs to be further explored as it may yield major changes in our understanding and treatment of severe psychotic disorders

Le système histaminergique : une cible pour de nouveaux traitements des deficits cognitifs

International audienceThe central effects of histamine are mediated by H1,H2 and H3 receptors. The H3 receptor inhibits histamine release in brain. Therefore, H3 receptor inverse agonists, by suppressing this brake, enhance histamine neuron activity.The histaminergic system plays a major role in cognition and H3 receptor inverse agonists are expected to be a potential therapeutics for cognitive deficits of Alzheimer’s disease (AD). They are eagerly awaited inasmuch as other treatments of the disease, such as tacrine or memantine, also enhance, through different mechanisms, histaminergic neurotransmission.An important loss of histaminergic neurons has been observed in AD. In contrast, levels of the histamine metabolite in the CSF of AD patients show that their global activity is decreased by only 25%. This indicates that activating histamine neurons in AD can be envisaged.L’histamine exerce ses effets centraux en activant des récepteurs H1,H2 et H3. Le récepteur H3 inhibe la liberation de l’histamine cérébrale. Ainsi, les agonistes inverses H3, en levant ce frein, augmentent l’activité des neurones à histamine.Le système histaminergique est un système majeur de la cognition et les agonistes inverses H3 sont pressentis comme thérapeutique potentielle des déficits cognitifs de la maladie d’Alzheimer (AD). Ils sont d’autant plus attendus que d’autres traitements de la maladie, tels que la tacrine ou la mémantine, augmentent aussi, mais par d’autres mécanismes, la neurotransmission histaminergique.Il existe une perte importante de neurones histaminergiques dans l’AD, mais la mesure des taux du métabolite de l’histamine dans le LCR de patients atteints d’AD montre que leur activité globale n’est diminuée que de 25 %. Ces données montrent qu’il devrait bien être possible d’activer les neurones histaminergiques dans l’AD

The DNA copy number of human endogenous retrovirus-W (MSRV-type) is increased in multiple sclerosis patients and is influenced by gender and disease severity.

BACKGROUND: Multiple sclerosis is an autoimmune disease more prevalent in women than in men. Multiple Sclerosis Associated Retrovirus element (MSRV) is a member of type-W endogenous retrovirus family (HERV-W), known to be associated to MS. Most HERVs are unable to replicate but MSRV expression associated with reverse-transcriptase activity in MS would explain reported DNA copy number increase in MS patients. A potential link between HERV-W copies on chromosome X and gender differential prevalence has been suggested. The present study addresses MSRV-type DNA load in relation with the gender differences and clinical status in MS and healthy controls. RESULTS: 178 MS patients (62.9% women) and 124 controls (56.5% women) were included. MSRV env load (copies/pg of DNA) was analyzed by real time qPCR with specific primers and probe for its env gene, in DNA from peripheral blood mononuclear cells (PBMCs). MSRV load was more elevated in MS patients than in controls (p = 4.15e-7). MS women presented higher MSRV load than control women (p = 0.009) and MS men also had higher load than control men (p = 2.77e-6). Besides, women had higher levels than men, both among patients (p = 0.007) and controls (p = 1.24e-6). Concordantly, EDSS and MSSS scores were higher among female patients with an elevated MSRV load (p = 0.03 and p = 0.04, respectively). CONCLUSIONS: MSRV increases its copy number in PBMC of MS patients and particularly in women with high clinical scores. This may explain causes underlying the higher prevalence of MS in women. The association with the clinical severity calls for further investigations on MSRV load in PBMCs as a biomarker for MS

MSRV DNA load MS diagnosis and sex.

<p><b>A)</b> MSRV DNA load is more elevated in PBMC of MS patients (n = 178) than in controls (n = 124) (ANOVA; p = 4.15e-7). B<b>)</b> MSRV DNA load is more elevated in MS women (n = 112) than in control women (n = 70) (ANOVA; p = 0.009), control men (n = 54) (ANOVA; p = 8.87e-14) and MS men (n = 66) (ANOVA; p = 0.007). MSRV DNA load is more elevated in control women (n = 70) than in control men (n = 54) (ANOVA; p = 1.24e-6). Points represent the mean and bars represent 95% Confidence Interval of Mean. MSRV DNA load represents MSRV copies/pg of DNA.</p

MSRV load and clinical evolution in women with MS.

<p><b>A)</b> The EDSS Score is higher among patients with a MSRV DNA load above the Cut-Off* (Cut-Off = 2.22, corresponding to 165 copies/pg of DNA) (n = 7) than below (n = 101). ANOVA; p = 0.032. <b>B)</b> MSSS score is higher among patients with a MSRV DNA load above the Cut-Off*(n = 7) than below (n = 99). ANOVA; p = 0.044. Points represent the mean and bars represent 95% Confidence Interval of Mean. MSRV load represents MSRV copies/pg of DNA. *Cut-Off = Mean _log10_{MSRV DNA}_Controls +2*S.D _{log10 MSRV DNA}_Controls; This represents the threshold above which the values are no longer within the range of the normal population.</p

Human endogenous retrovirus type W envelope expression in blood and brain cells provides new insights into multiple sclerosis disease

Background: The envelope protein from multiple sclerosis (MS) associated retroviral element (MSRV), a member of the Human Endogenous Retroviral family ‘W’ (HERV-W), induces dysimmunity and inflammation. Objective: The objective of this study was to confirm and specify the association between HERV-W/MSRV envelope (Env) expression and MS. Methods: 103 MS, 199 healthy controls (HC) and controls with other neurological diseases (28), chronic infections (30) or autoimmunity (30) were analysed with an immunoassay detecting Env in serum. Env RNA or DNA copy numbers in peripheral blood mononuclear cells (PBMC) were determined by a quantitative polymerase chain reaction (PCR). Env was detected by immunohistology in the brains of patients with MS with three specific monoclonals. Results: Env antigen was detected in a serum of 73% of patients with MS with similar prevalence in all clinical forms, and not in chronic infection, systemic lupus, most other neurological diseases and healthy donors (p&lt;0.01). Cases with chronic inflammatory demyelinating polyneuropathy (5/8) and rare HC (4/103) were positive. RNA expression in PBMC and DNA copy numbers were significantly elevated in patients with MS versus HC (p&lt;0.001). In patients with MS, DNA copy numbers were significantly increased in chronic progressive MS (secondary progressive MS vs relapsing–remitting MS (RRMS) p&lt;0.001; primary progressive MS vs RRMS –&lt;0.02). Env protein was evidenced in macrophages within MS brain lesions with particular concentrations around vascular elements. Conclusion: The association between MS disease and the MSRV-type HERV-W element now appears quite strong, as evidenced ex-vivo from serum and PBMC with post-mortem confirmation in brain lesions. Chronic progressive MS, RRMS and clinically isolated syndrome show different ELISA (Enzyme-Linked Immunosorbent Assay) and/or PCR profiles suggestive of an increase with disease evolution, and amplicon sequencing confirms the association with particular HERV-W elements