The causes of multiple sclerosis and amyotrophic lateral sclerosis have long remained elusive. A new category of pathogenic components, normally dormant within human genomes, has been identified: human endogenous retroviruses (HERVs). These represent ∼8% of the human genome, and environmental factors have reproducibly been shown to trigger their expression. The resulting production of envelope (Env) proteins from HERV-W and HERV-K appears to engage pathophysiological pathways leading to the pathognomonic features of MS and ALS, respectively. Pathogenic HERV elements may thus provide a missing link in understanding these complex diseases. Moreover, their neutralization may represent a promising strategy to establish novel and more powerful therapeutic approaches.
Our findings suggest that ENV-mediated induction of nitrosative stress via activation of TLR4 results in an overall reduction of the oligodendroglial differentiation capacity, thereby contributing to remyelination failure. Therefore, pharmacological or antibody-mediated inhibition of ENV may prevent the blockade of myelin repair in the diseased or injured central nervous system.
Fingolimod (also known as FTY720) is an orally available sphingosine-1-phosphate (S1P) receptor modulator that has unique and potent immunoregulatory properties. Mechanistic studies indicate that on phosphorylation fingolimod can bind with high affinity to S1P(1) receptors. Persistent modulation of lymphocyte S1P(1) receptors by fingolimod and the subsequent internalization of these receptors inhibits lymphocyte egress from the lymph nodes, and prevents these cells from infiltrating inflammatory lesions in the CNS. Results of two phase III studies--FREEDOMS and TRANSFORMS--support previous phase II trial observations indicating that fingolimod exerts powerful anti-inflammatory effects in relapsing-remitting multiple sclerosis (MS). Fingolimod might, therefore, be one of the first orally active drug therapies available for the treatment of relapsing-remitting MS. Moreover, results from preclinical studies suggest that fingolimod might promote neural repair in vivo. In this article, we review the background to these findings, present the proposed immunological and neurobiological profile of fingolimod, discuss the data from the FREEDOMS and TRANSFORMS trials, and provide an expert opinion regarding the future of next-generation S1P receptor modulators for MS therapy.
Axonal degeneration is central to clinical disability and disease progression in multiple sclerosis (MS). Myeloid cells such as brain-resident microglia and blood-borne monocytes are thought to be critically involved in this degenerative process. However, the exact underlying mechanisms have still not been clarified. We have previously demonstrated that human endogenous retrovirus type W (HERV-W) negatively affects oligodendroglial precursor cell (OPC) differentiation and remyelination via its envelope protein pathogenic HERV-W (pHERV-W) ENV (formerly MS-associated retrovirus [MSRV]-ENV). In this current study, we investigated whether pHERV-W ENV also plays a role in axonal injury in MS. We found that in MS lesions, pHERV-W ENV is present in myeloid cells associated with axons. Focusing on progressive disease stages, we could then demonstrate that pHERV-W ENV induces a degenerative phenotype in microglial cells, driving them toward a close spatial association with myelinated axons. Moreover, in pHERV-W ENV-stimulated myelinated cocultures, microglia were found to structurally damage myelinated axons. Taken together, our data suggest that pHERV-W ENV-mediated microglial polarization contributes to neurodegeneration in MS. Thus, this analysis provides a neurobiological rationale for a recently completed clinical study in MS patients showing that antibody-mediated neutralization of pHERV-W ENV exerts neuroprotective effects.
One of the most striking features of the injured mature peripheral nervous system is the ability to regenerate. The lesioned peripheral nervous system displays stereotypic histopathological reactions indicating the activation of a co-ordinated lesion-induced gene expression programme. Previous research has already identified molecular components of this axonal switch from a mature transmitting to a regenerative growth mode. The observed alterations in gene expression within the lesioned distal nerve stump were largely attributed to recapitulated developmental processes. However, to our knowledge, this hypothesis has not been proven systematically. Most of the stereotypic molecular and cellular reactions during nerve development and repair can be assigned to specific time windows. Consequently, we have compared gene expression profiles of both paradigms at six different time-points each by means of cDNA array hybridization. Our data identified injury-specific molecular reactions and revealed to what extent developmental mechanisms are reactivated in response to nerve lesion. Ninety-one genes (47% of the regeneration-associated genes) were found to be significantly regulated in both paradigms, suggesting that regeneration only partially recapitulates development and that approximately half of the regulated genes are part of a regenerationdependent programme. Interestingly, mainly genes encoding signal transducers or factors involved in processes such as cell death, immune response, transport and transcriptional regulation showed injury-specific gene expression. Keywords: cDNA array analysis, development, gene expression profiling, nerve injury, sciatic nerve regeneration. Adult peripheral nerves in mammals have an intrinsic capacity to regenerate after axotomy. This spontaneous regeneration potential distinguishes the peripheral nervous system from the CNS. Recent advances in the study of peripheral nerve regeneration have revealed that successful neuronal survival and target reinnervation depend on both the intrinsic regenerative capacity of peripheral axons and the presence of a growth-permissive environment.DNA array-based expression profiling allows identification of the spectrum of genes expressed during peripheral nerve regeneration. Recently, several studies were published describing axotomy-induced changes in peripheral nerve gene expression. However, these studies mainly focused on those transcriptional changes that were induced in the cell bodies of the axotomized sensory or spinal motor neurones (Fan et al. 2001;Kim et al. 2001;Bonilla et al. 2002;Costigan et al. 2002;Nagarajan et al. 2002;Xiao et al. 2002;Cameron et al. 2003). Besides a previous study published by our laboratory (Bosse et al. Abbreviations used: ApoD, apolipoprotein D; AP-1, adaptor protein complex AP-1; ATF, activating transcription factor; bcl2, apoptosis regulator protein Bcl-2 like protein 1; BMP-2, bone morphogenic protein; bZIP, basic leucine zipper transcription factor; C/EBPd, CCAAT/ enhancer binding protein delta; CREB...
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