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Andreas Junker, MD
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Contact: andreas.junker@gmx.net |
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Research activity |
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Research topic: Multiple Sclerosis
Background
Multiple sclerosis (MS) is the most frequent demyelinating disease of the central nervous system (CNS). It affects approximately two million people worldwide, with major individual and socio-economic consequences. MS lesions are characterized by chronic inflammation, demyelination with limited remyelination, and axonal loss. The lesions are heterogeneous with respect to inflammatory activity and therefore early active lesions, chronic active lesions, and chronic inactive lesions are distinguished. It has been shown that extensive axonal damage and loss occurs within active lesions. This axonal loss is now considered to be mainly responsible for the permanent disability developing during the disease. Different mechanisms probably contribute to the axonal loss, namely missing trophic support by myelin, toxic mediators being produced during inflammation such as NO, and anti-axonal immune response. The integrity of the myelin sheath is an essential precondition for long-term axonal preservation. Until now, it has not been understood how effective remyelination and axonal protection can be therapeutically achieved in MS patients, and therefore it is necessary to better understand the pathophysiological processes in the lesions. A key to accurately classify MS pathophysiological processes is a better understanding of epigenetic mechanisms, for example based on microRNA (miRNA) analysis. MiRNAs are endogenous 19–25 nucleotide RNAs that have emerged as a novel class of important gene-regulatory molecules involved in many critical developmental and cellular functions. MiRNAs provide a system of transcript level regulation. It is estimated that a few hundred miRNAs in humans regulate the transcript level of about 1/3 of all genes by typically binding to the 3’ untranslated region of transcripts and regulating their stability.
Research projects Molecular analysis of well characterized lesions teaches us about both pathomechanisms and repair strategies. We strongly focus on the analysis of MS autopsy tissue in particular on morphological aspects of the lesions.
Cortical demyelination For instance, we found that extensive band-like subpial cortical demyelination could only be detected in multiple sclerosis (Junker et al., 2020). However, in other demyelinating diseases such as acute disseminated encephalomyelitis (ADEM), neuromyelitis optica (NMO), progressive multifocal leukoencephalopathy (PML) and central pontine myelinolysis (CPM), cortical demyelination could also be detected, but these diseases show a specific histopathological pattern that is fundamentally different from MS.
Oxidative stress Since oxidative damage is obviously a major contributor to tissue damage in multiple sclerosis, it remains important to understand its molecular basis in detail paving the way for targeted future therapies. Based on this we investigated the expression of the anti-oxidative molecule PRDX2 in MS- lesions (Voigt et al., 2017). PRDX2 presumably fulfills an essential protective function against oxidative damage in astrocytes.
Failed remyelination: Along with protection against tissue damage, a therapeutic focus on tissue regeneration is needed in the coming years. The deficient remyelination of multiple sclerosis lesions will certainly play a major role as a target of future therapies. Early remyelination in particular may play an important role in axon protection (Schultz et al., 2017). BMP4, as the most prominently expressed molecule from the group of BMPs in human brains, could occupy a particularly prominent position as a therapeutic target in this context. We found that remyelination of MS lesions occurs in areas where not only BMP4 but also its antagonist Noggin is present (Harnisch et al., 2019). This observation implies that successful remyelination is associated with antagonization of BMP4.
MicroRNA signatures A different approach to pathophysiological interactions in lesions is shown in our studies on miRNAs. Our focus is on the investigation of miRNAs and their biological effects in MS-brain (Junker, 2011; Junker et al., 2011; Teuber-Hanselmann et al., 2020). Thus, we were able to demonstrate miRNA expression profiles in multiple sclerosis lesions of gray and white matter (Fritsche et al., 2019; Junker et al., 2009). In fact, the studies presented here were the first publications worldwide of miRNA signatures in gray and white matter lesions in multiple sclerosis. Thereby we could describe a pro-inflammatory effect of miR-155, the most upregulated miRNA in acute MS lesion (Junker et al., 2009). This miRNA regulates the immunomodulatory surface protein CD47 (Junker et al., 2009). Our work extended the previously established concepts of macrophage activity in multiple sclerosis lesions to the level of miRNA-mediated gene regulation. Furthermore, we demonstrated that the synaptic protein Syt7, which accumulates in neuronal cell bodies in MS and whose axonal transport appears to be impaired, is regulated by miRNAs (Fritsche et al., 2019).
Our current research projects focus on molecular characteristics of in particular gray matter lesions. Of particular interest for us is the specific cytokine milieu in these lesions. Furthermore, investigations regarding defective remyelination in MS lesions are ongoing by investigating microRNA targets such as CD47.
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